CanVIG-UK
combinations
The reference for which CanVIG-UK evidence codes may be used together. Consensus Specification v3.30, 27 August 2026, pages 19-20.
Consensus Specification v3.30, 27 August 2026, pages 19-20.
CanVIG-UK guidanceSpecification PDF
This page is a lookup of CanVIG-UK Consensus Specification v3.30, 27 August 2026, pages 19-20. The specification PDF is the source.
Towards pathogenicity
| Codes | Status | Specification |
|---|---|---|
| PVS1 + PM4 Null variant and Protein length | Not permitted | PM4 is used for in-frame deletions/insertions that are small (≤1 exon length), PVS1 is used for larger in-frame multi-exon deletions/duplications. |
| PVS1 + PS2 Null variant and De novo confirmed | Permitted: simple | |
| PM4 + PS2 Protein length and De novo confirmed | Permitted: simple | |
| PVS1 + PM6 Null variant and De novo unconfirmed | Permitted: simple | |
| PM4 + PM6 Protein length and De novo unconfirmed | Permitted: simple | |
| PS2 + PM6 De novo confirmed and De novo unconfirmed | Not possible (different variant types) | |
| PVS1 + PP4 Null variant and Phenotype specificity | Permitted: simple | |
| PM4 + PP4 Protein length and Phenotype specificity | Permitted: simple | |
| PS2 + PP4 De novo confirmed and Phenotype specificity | Permitted: simple | |
| PM6 + PP4 De novo unconfirmed and Phenotype specificity | Permitted: simple | |
| PVS1 + PS4 Null variant and Case-control | Permitted: simple | |
| PM4 + PS4 Protein length and Case-control | Permitted: simple | |
| PS2 + PS4 De novo confirmed and Case-control | Permitted: simple | |
| PM6 + PS4 De novo unconfirmed and Case-control | Permitted: simple | |
| PP4 + PS4 Phenotype specificity and Case-control | Caution | Can not be combined if case-counting used for PS4 and phenotypic features have been included in case-definition. |
| PVS1 + PM2 Null variant and Absent from controls | Permitted: simple | |
| PM4 + PM2 Protein length and Absent from controls | Permitted: simple | |
| PS2 + PM2 De novo confirmed and Absent from controls | Permitted: simple | |
| PM6 + PM2 De novo unconfirmed and Absent from controls | Permitted: simple | |
| PP4 + PM2 Phenotype specificity and Absent from controls | Permitted: simple | |
| PS4 + PM2 Case-control and Absent from controls | Caution | The same control series can not be used for PM2 and PS4. Can be combined where a second control series is available. |
| PVS1 + PP2 Null variant and Low benign missense | Not possible (different variant types) | |
| PM4 + PP2 Protein length and Low benign missense | Not possible (different variant types) | |
| PS2 + PP2 De novo confirmed and Low benign missense | Permitted: simple | |
| PM6 + PP2 De novo unconfirmed and Low benign missense | Permitted: simple | |
| PP4 + PP2 Phenotype specificity and Low benign missense | Permitted: simple | |
| PS4 + PP2 Case-control and Low benign missense | Permitted: simple | |
| PM2 + PP2 Absent from controls and Low benign missense | Permitted: simple | |
| PVS1 + PM1 Null variant and Hot spot | Not permitted | PM1 is reserved for missense/small insertions-deletions. |
| PM4 + PM1 Protein length and Hot spot | Permitted | PM1 can be used for missense or small (localised) insertions or deletions. |
| PS2 + PM1 De novo confirmed and Hot spot | Permitted: simple | |
| PM6 + PM1 De novo unconfirmed and Hot spot | Permitted: simple | |
| PP4 + PM1 Phenotype specificity and Hot spot | Permitted: simple | |
| PS4 + PM1 Case-control and Hot spot | Permitted: simple | |
| PM2 + PM1 Absent from controls and Hot spot | Permitted: simple | |
| PP2 + PM1 Low benign missense and Hot spot | Not permitted | PP2 is used for constraint at gene level, PM1 is used for constraint at domain level. This has been updated from recommendations in Garett et al 2020 with emergence of more evolved analyses of case-control constraint. |
| PVS1 + PM5 Null variant and Same residue | Caution | PM5 application is reserved for missense variants, except where use of PM5 and PVS1 in combination is recommended by gene-specific guidance. |
| PM4 + PM5 Protein length and Same residue | Caution | PM5 application is reserved for missense variants, except where use of PM5 and PVS1 in combination is recommended by gene-specific guidance. |
| PS2 + PM5 De novo confirmed and Same residue | Permitted: simple | |
| PM6 + PM5 De novo unconfirmed and Same residue | Permitted: simple | |
| PP4 + PM5 Phenotype specificity and Same residue | Permitted: simple | |
| PS4 + PM5 Case-control and Same residue | Permitted: simple | |
| PM2 + PM5 Absent from controls and Same residue | Permitted: simple | |
| PP2 + PM5 Low benign missense and Same residue | Not permitted | Where points are awarded for substitution at the same residue/ of the same amino acid, additional points can not be awarded for constraint at gene/domain level. A variant for which functional data is used for PS3 or BS3 can not be awarded PM1, as typically functional data informs delineation of a domain/hot-spot. |
| PM1 + PM5 Hot spot and Same residue | Not permitted | Where points are awarded for substitution at the same residue/ of the same amino acid, additional points can not be awarded for constraint at gene/domain level. A variant for which functional data is used for PS3 or BS3 can not be awarded PM1, as typically functional data informs delineation of a domain/hot-spot. |
| PVS1 + PS1 Null variant and Same aa change | Caution | For application of PS1 in the context of splicing, predictive tools (PP3 or PVS1) should demonstrate a predicted impact on splicing as per the Walker et al., 2023 guidance. Codes may be applied in combination (PS1 + PP3 or PS1 + PVS1), please see the table in the PS1 section of this document for examples. |
| PM4 + PS1 Protein length and Same aa change | Not possible (different variant types) | |
| PS2 + PS1 De novo confirmed and Same aa change | Permitted: simple | |
| PM6 + PS1 De novo unconfirmed and Same aa change | Permitted: simple | |
| PP4 + PS1 Phenotype specificity and Same aa change | Permitted: simple | |
| PS4 + PS1 Case-control and Same aa change | Permitted: simple | |
| PM2 + PS1 Absent from controls and Same aa change | Permitted: simple | |
| PP2 + PS1 Low benign missense and Same aa change | Not permitted | Where points are awarded for substitution at the same residue/ of the same amino acid, additional points can not be awarded for constraint at gene/domain level. A variant for which functional data is used for PS3 or BS3 can not be awarded PM1, as typically functional data informs delineation of a domain/hot-spot. |
| PM1 + PS1 Hot spot and Same aa change | Not permitted | Where points are awarded for substitution at the same residue/ of the same amino acid, additional points can not be awarded for constraint at gene/domain level. A variant for which functional data is used for PS3 or BS3 can not be awarded PM1, as typically functional data informs delineation of a domain/hot-spot. |
| PM5 + PS1 Same residue and Same aa change | Not permitted | PS1 supersedes PM5. |
| PVS1 + PP3 Null variant and In silico | Not permitted | PVS1/PM4 are awarded for prediction of a pro-pathogenicity mechanism; PP3 can not be used additionally. |
| PM4 + PP3 Protein length and In silico | Not permitted | PVS1/PM4 are awarded for prediction of a pro-pathogenicity mechanism; PP3 can not be used additionally. |
| PS2 + PP3 De novo confirmed and In silico | Permitted: simple | |
| PM6 + PP3 De novo unconfirmed and In silico | Permitted: simple | |
| PP4 + PP3 Phenotype specificity and In silico | Permitted: simple | |
| PS4 + PP3 Case-control and In silico | Permitted: simple | |
| PM2 + PP3 Absent from controls and In silico | Permitted: simple | |
| PP2 + PP3 Low benign missense and In silico | Permitted: simple | |
| PM1 + PP3 Hot spot and In silico | Permitted: simple | |
| PM5 + PP3 Same residue and In silico | Permitted: simple | |
| PS1 + PP3 Same aa change and In silico | Caution | For application of PS1 in the context of splicing, predictive tools (PP3 or PVS1) should demonstrate a predicted impact on splicing as per the Walker et al., 2023 guidance. Codes may be applied in combination (PS1 + PP3 or PS1 + PVS1), please see the table in the PS1 section of this document for examples. |
| PVS1 + PS3 Null variant and Functional (Protein Impact) | Restriction | Evidence from predictive tools (except for splicing impact predictors) may be used in combination with evidence from protein impact assays (PS3). |
| PM4 + PS3 Protein length and Functional (Protein Impact) | Restriction | Evidence from predictive tools (except for splicing impact predictors) may be used in combination with evidence from protein impact assays (PS3). |
| PS2 + PS3 De novo confirmed and Functional (Protein Impact) | Permitted: simple | |
| PM6 + PS3 De novo unconfirmed and Functional (Protein Impact) | Permitted: simple | |
| PP4 + PS3 Phenotype specificity and Functional (Protein Impact) | Permitted: simple | |
| PS4 + PS3 Case-control and Functional (Protein Impact) | Permitted: simple | |
| PM2 + PS3 Absent from controls and Functional (Protein Impact) | Permitted: simple | |
| PP2 + PS3 Low benign missense and Functional (Protein Impact) | Permitted: simple | |
| PM1 + PS3 Hot spot and Functional (Protein Impact) | Not permitted | Where points are awarded for substitution at the same residue/ of the same amino acid, additional points can not be awarded for constraint at gene/domain level. A variant for which functional data is used for PS3 or BS3 can not be awarded PM1, as typically functional data informs delineation of a domain/hot-spot. |
| PM5 + PS3 Same residue and Functional (Protein Impact) | Restriction | PM5 and PS1 can only be applied in combination with PS3 if the reference variant can be classified as (likely) pathogenic without the use of functional data, and no splicing effect is predicted with prediction tools or suggested through results from functional assays. |
| PS1 + PS3 Same aa change and Functional (Protein Impact) | Restriction | PM5 and PS1 can only be applied in combination with PS3 if the reference variant can be classified as (likely) pathogenic without the use of functional data, and no splicing effect is predicted with prediction tools or suggested through results from functional assays. |
| PP3 + PS3 In silico and Functional (Protein Impact) | Restriction | Evidence from predictive tools (except for splicing impact predictors) may be used in combination with evidence from protein impact assays (PS3). |
| PVS1 + PVS1_RNA Null variant and Functional (Splicing) | Not permitted | If PVS1_RNA has been applied, predictive codes (PP3, PM4, and PVS1) may not also be applied for splicing impact prediction, although results from splicing predictions may be used to validate application of PVS1_RNA (per Walker et al, 2023). |
| PM4 + PVS1_RNA Protein length and Functional (Splicing) | Not permitted | If PVS1_RNA has been applied, predictive codes (PP3, PM4, and PVS1) may not also be applied for splicing impact prediction, although results from splicing predictions may be used to validate application of PVS1_RNA (per Walker et al, 2023). |
| PS2 + PVS1_RNA De novo confirmed and Functional (Splicing) | Permitted: simple | |
| PM6 + PVS1_RNA De novo unconfirmed and Functional (Splicing) | Permitted: simple | |
| PP4 + PVS1_RNA Phenotype specificity and Functional (Splicing) | Permitted: simple | |
| PS4 + PVS1_RNA Case-control and Functional (Splicing) | Permitted: simple | |
| PM2 + PVS1_RNA Absent from controls and Functional (Splicing) | Permitted: simple | |
| PP2 + PVS1_RNA Low benign missense and Functional (Splicing) | Permitted: simple | |
| PM1 + PVS1_RNA Hot spot and Functional (Splicing) | Permitted: simple | |
| PM5 + PVS1_RNA Same residue and Functional (Splicing) | Permitted: simple | |
| PS1 + PVS1_RNA Same aa change and Functional (Splicing) | Caution | Per advice from the ClinGen SVI Splicing Subgroup Response to Feedback document, PS1 and PVS1_RNA may be used in combination provided that there is a relevant pathogenic variant with the same predicted impact as the variant under assessment (for further details, see: the table in the PS1 section of this document, Table 2 of Walker et al., 2023, and the ClinGen SVI Splicing Subgroup Response to Feedback document). |
| PP3 + PVS1_RNA In silico and Functional (Splicing) | Not permitted | If PVS1_RNA has been applied, predictive codes (PP3, PM4, and PVS1) may not also be applied for splicing impact prediction, although results from splicing predictions may be used to validate application of PVS1_RNA (per Walker et al, 2023). |
| PS3 + PVS1_RNA Functional (Protein Impact) and Functional (Splicing) | Restriction | PS3 and PVS1_RNA may be used in combination only if the two criteria together do not exceed 8 evidence points (very strong). For example, PS3_MOD + PVS1_RNA_STR (total of 6 points) is permitted, but PS3_MOD + PVS1_RNA_VSTR (total of 10 points) is not. |
| PVS1 + PM3 Null variant and In trans | Permitted: simple | |
| PM4 + PM3 Protein length and In trans | Permitted: simple | |
| PS2 + PM3 De novo confirmed and In trans | Permitted: simple | |
| PM6 + PM3 De novo unconfirmed and In trans | Permitted: simple | |
| PP4 + PM3 Phenotype specificity and In trans | Caution | PP4 can not be used for subphenotypic elements which themselves have been used in the case-definition of specific phenotype for PM3. |
| PS4 + PM3 Case-control and In trans | Permitted: simple | |
| PM2 + PM3 Absent from controls and In trans | Permitted: simple | |
| PP2 + PM3 Low benign missense and In trans | Permitted: simple | |
| PM1 + PM3 Hot spot and In trans | Permitted: simple | |
| PM5 + PM3 Same residue and In trans | Permitted: simple | |
| PS1 + PM3 Same aa change and In trans | Permitted: simple | |
| PP3 + PM3 In silico and In trans | Permitted: simple | |
| PS3 + PM3 Functional (Protein Impact) and In trans | Permitted: simple | |
| PVS1_RNA + PM3 Functional (Splicing) and In trans | Permitted: simple | |
| PVS1 + PP1 Null variant and Co-segregation | Permitted: simple | |
| PM4 + PP1 Protein length and Co-segregation | Permitted: simple | |
| PS2 + PP1 De novo confirmed and Co-segregation | Permitted: simple | |
| PM6 + PP1 De novo unconfirmed and Co-segregation | Permitted: simple | |
| PP4 + PP1 Phenotype specificity and Co-segregation | Caution | PP4 can not be used for subphenotypic elements which themselves have been used in the case-definition of specific phenotype for segregation. |
| PS4 + PP1 Case-control and Co-segregation | Permitted: simple | |
| PM2 + PP1 Absent from controls and Co-segregation | Permitted: simple | |
| PP2 + PP1 Low benign missense and Co-segregation | Permitted: simple | |
| PM1 + PP1 Hot spot and Co-segregation | Permitted: simple | |
| PM5 + PP1 Same residue and Co-segregation | Permitted: simple | |
| PS1 + PP1 Same aa change and Co-segregation | Permitted: simple | |
| PP3 + PP1 In silico and Co-segregation | Permitted: simple | |
| PS3 + PP1 Functional (Protein Impact) and Co-segregation | Permitted: simple | |
| PVS1_RNA + PP1 Functional (Splicing) and Co-segregation | Permitted: simple | |
| PM3 + PP1 In trans and Co-segregation | Caution | If identification in trans is part of evaluation of co-segregation, these elements can not both be counted. |
Towards benignity
| Codes | Status | Specification |
|---|---|---|
| BA1/BS1 + BS2 Allele frequency and Healthy homozygote | Permitted: simple | |
| BA1/BS1 + BS3 Allele frequency and Functional (Protein Impact) | Permitted: simple | |
| BS2 + BS3 Healthy homozygote and Functional (Protein Impact) | Permitted: simple | |
| BA1/BS1 + BP7_RNA Allele frequency and Functional (Splicing) | Permitted: simple | |
| BS2 + BP7_RNA Healthy homozygote and Functional (Splicing) | Permitted: simple | |
| BS3 + BP7_RNA Functional (Protein Impact) and Functional (Splicing) | Restricted | BS3 and BP7_RNA may be used in combination only if the two criteria together do not exceed 8 evidence points (very strong). |
| BA1/BS1 + BS4 Allele frequency and Non-segregation | Permitted: simple | |
| BS2 + BS4 Healthy homozygote and Non-segregation | Caution | If identification in trans is part of evaluation of co-segregation, these elements can not both be counted. |
| BS3 + BS4 Functional (Protein Impact) and Non-segregation | Permitted: simple | |
| BP7_RNA + BS4 Functional (Splicing) and Non-segregation | Permitted: simple | |
| BA1/BS1 + BP1 Allele frequency and Missense in unconstrained region | Permitted: simple | |
| BS2 + BP1 Healthy homozygote and Missense in unconstrained region | Permitted: simple | |
| BS3 + BP1 Functional (Protein Impact) and Missense in unconstrained region | Permitted: simple | |
| BP7_RNA + BP1 Functional (Splicing) and Missense in unconstrained region | Permitted: simple | |
| BS4 + BP1 Non-segregation and Missense in unconstrained region | Permitted: simple | |
| BA1/BS1 + BP2 Allele frequency and observation in trans/cis | Permitted: simple | |
| BS2 + BP2 Healthy homozygote and observation in trans/cis | Not permitted | In a recessive context BS2 is used for homozygosity; BP2 for heterozygosity. |
| BS3 + BP2 Functional (Protein Impact) and observation in trans/cis | Permitted: simple | |
| BP7_RNA + BP2 Functional (Splicing) and observation in trans/cis | Permitted: simple | |
| BS4 + BP2 Non-segregation and observation in trans/cis | Caution | If identification in trans is part of evidence against co-segregation, these elements can not both be counted. |
| BP1 + BP2 Missense in unconstrained region and observation in trans/cis | Permitted: simple | |
| BA1/BS1 + BP3 Allele frequency and In-frame deletion (repetitive region) | Permitted: simple | |
| BS2 + BP3 Healthy homozygote and In-frame deletion (repetitive region) | Permitted: simple | |
| BS3 + BP3 Functional (Protein Impact) and In-frame deletion (repetitive region) | Permitted: simple | |
| BP7_RNA + BP3 Functional (Splicing) and In-frame deletion (repetitive region) | Permitted: simple | |
| BS4 + BP3 Non-segregation and In-frame deletion (repetitive region) | Permitted: simple | |
| BP1 + BP3 Missense in unconstrained region and In-frame deletion (repetitive region) | Not possible (different variant types) | |
| BP2 + BP3 observation in trans/cis and In-frame deletion (repetitive region) | Permitted: simple | |
| BA1/BS1 + BP4 Allele frequency and In silico | Permitted: simple | |
| BS2 + BP4 Healthy homozygote and In silico | Permitted: simple | |
| BS3 + BP4 Functional (Protein Impact) and In silico | Restricted | Evidence from predictive tools (except for splicing impact predictors) is permitted where a protein impact assay within PS3 is applied. |
| BP7_RNA + BP4 Functional (Splicing) and In silico | Permitted: simple | |
| BS4 + BP4 Non-segregation and In silico | Permitted: simple | |
| BP1 + BP4 Missense in unconstrained region and In silico | Permitted: simple | |
| BP2 + BP4 observation in trans/cis and In silico | Permitted: simple | |
| BP3 + BP4 In-frame deletion (repetitive region) and In silico | Not permitted | BP3 already recognises sequence context. |
| BA1/BS1 + BP5 Allele frequency and Alternative cause | Permitted: simple | |
| BS2 + BP5 Healthy homozygote and Alternative cause | Permitted: simple | |
| BS3 + BP5 Functional (Protein Impact) and Alternative cause | Permitted: simple | |
| BP7_RNA + BP5 Functional (Splicing) and Alternative cause | Permitted: simple | |
| BS4 + BP5 Non-segregation and Alternative cause | Caution | BP5 can not be used for alternative explanation where also used in same individual as evidence for non-segregation. |
| BP1 + BP5 Missense in unconstrained region and Alternative cause | Permitted: simple | |
| BP2 + BP5 observation in trans/cis and Alternative cause | Not permitted | together. |
| BP3 + BP5 In-frame deletion (repetitive region) and Alternative cause | Permitted: simple | |
| BP4 + BP5 In silico and Alternative cause | Permitted: simple | |
| BA1/BS1 + BP7 Allele frequency and Synonymous | Permitted: simple | |
| BS2 + BP7 Healthy homozygote and Synonymous | Permitted: simple | |
| BS3 + BP7 Functional (Protein Impact) and Synonymous | Permitted: simple | |
| BP7_RNA + BP7 Functional (Splicing) and Synonymous | Permitted: simple | |
| BS4 + BP7 Non-segregation and Synonymous | Permitted: simple | |
| BP1 + BP7 Missense in unconstrained region and Synonymous | Not possible (different variant types) | |
| BP2 + BP7 observation in trans/cis and Synonymous | Permitted: simple | |
| BP3 + BP7 In-frame deletion (repetitive region) and Synonymous | Not possible (different variant types) | |
| BP4 + BP7 In silico and Synonymous | Caution | Absence of predicted splicing effect must be confirmed using in silico tools. |
| BP5 + BP7 Alternative cause and Synonymous | Permitted: simple |
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