# NM_006366.3(CAP2):c.443T>C (p.Val148Ala)

https://sugi.bio/variant/cap2-p-val148ala

## Summary

**CAP2 p.Val148Ala (c.443T>C)** is classified **Uncertain significance** in CAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-17). AlphaMissense: likely pathogenic (0.7623); Ultra-rare (popmax 0.0133%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs762359662 · 1 submitter · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0133%, afr)

## 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.Val148Ala |
| Coding change (HGVS c.) | c.443T>C |
| MANE Select transcript | [NM_019894](https://www.ncbi.nlm.nih.gov/nuccore/NM_019894) (variant reported on NM_006366) |
| dbSNP | [rs762359662](https://www.ncbi.nlm.nih.gov/snp/rs762359662/) |
| Variant type | single nucleotide variant |
| Location | chr6:17507311-17507311 (GRCh38) |
| ClinVar | [VCV2522311](https://www.ncbi.nlm.nih.gov/clinvar/variation/2522311/) |

**All HGVS expressions:** `NC_000006.11:g.17507542T>C`, `NC_000006.12:g.17507311T>C`, `NM_001363533.2:c.301-31958T>C`, `NM_001363534.2:c.365T>C`, `NM_006366.3:c.443T>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.7623)
- REVEL 0.31 (indeterminate)
- SaProt LLR -8.139 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- Conservation: phyloP 6.117, GERP 1.88, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 8%** most-pathogenic-predicted substitutions in CAP2 (of 2,583 modeled).
- CADD: **PHRED 25.9**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0133%** (afr) · FAF95 0.00723% · FAF99 0.0055% · 10/74,940 in the highest group · 10/1,614,008 alleles overall — ultra-rare (popmax 0.0133%, afr).

*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 **148** lies in a disulfide bond; 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.Val148Ala 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 2023-05-17.

**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 | 2023-05-17 |

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

## Similar variants {#similar}

Related CAP2 variant pages (same residue, condition, or type): [CAP2 p.Val148Leu](/variant/cap2-p-val148leu), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 2522311). 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.*