# NM_006366.3(CAP2):c.307G>A (p.Val103Met)

https://sugi.bio/variant/cap2-p-val103met

## Summary

**CAP2 p.Val103Met (c.307G>A)** is classified **Uncertain significance** in CAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-10). AlphaMissense: likely benign (0.078); Ultra-rare (popmax 0.0253%, sas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0253%, sas)

## For patients & families {#patients}

This is a change in the CAP2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CAP2](https://sugi.bio/atlas/gene/CAP2/) |
| Protein change (HGVS p.) | p.Val103Met |
| Coding change (HGVS c.) | c.307G>A |
| MANE Select transcript | [NM_006366](https://www.ncbi.nlm.nih.gov/nuccore/NM_006366) |
| Variant type | single nucleotide variant |
| Location | chr6:17507175-17507175 (GRCh38) |
| ClinVar | [VCV3484688](https://www.ncbi.nlm.nih.gov/clinvar/variation/3484688/) |

**All HGVS expressions:** `NC_000006.11:g.17507406G>A`, `NC_000006.12:g.17507175G>A`, `NM_001363533.2:c.301-32094G>A`, `NM_001363534.2:c.229G>A`, `NM_006366.3:c.307G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.078)
- REVEL 0.101 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -2.221 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.25) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 5.009, GERP 0.68, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.9**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.25**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 6 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.0253%** (sas) · FAF95 0.0172% · FAF99 0.0146% · 23/91,086 in the highest group · 38/1,614,172 alleles overall — ultra-rare (popmax 0.0253%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0253% | 3,960 |
| Remaining individuals (not grpmax-eligible) | 0.0112% | 8,930 |
| East Asian | 0.00891% | 11,222 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,606 |
| European (non-Finnish) | 0.000254% | 393,340 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Protein context {#protein}

Residue **103** lies in the srcr domain.

AlphaFold model confidence (whole protein): pLDDT 88.01, 67% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of CAP2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CAP2's established molecular role includes serine-type peptidase activity. p.Val103Met falls in the srcr domain.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** serine-type peptidase activity.

**Biological process:** proteolysis, regulation of gene expression, protein processing, negative regulation of growth rate, positive regulation of viral entry into host cell.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-08-10.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-08-10 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CAP2 variant pages (same residue, condition, or type): [CAP2 p.Arg17His](/variant/cap2-p-arg17his), [CAP2 p.His203Arg](/variant/cap2-p-his203arg), [TMPRSS4 p.Ala44Val](/variant/tmprss4-p-ala44val), [CAP2 c.1003-5T>G](/variant/cap2-c-1003-minus-5t-g), [CAP2 p.Ala162Thr](/variant/cap2-p-ala162thr), [CAP2 p.Ala262Pro](/variant/cap2-p-ala262pro), [CAP2 p.Ala272Thr](/variant/cap2-p-ala272thr), [CAP2 p.Ala294Thr](/variant/cap2-p-ala294thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 3484688). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*