Is CAP2 p.Ser134Leu (c.401C>T) pathogenic?

CAP2 p.Ser134Leu (c.401C>T) is classified Uncertain significance in CAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-22). AlphaMissense: likely pathogenic (0.8961); Very rare (popmax 0.00666%, afr).

How common is CAP2 p.Ser134Leu (c.401C>T) in the general population?

CAP2 p.Ser134Leu (c.401C>T) is very rare (popmax 0.00666%, afr) (gnomAD).

What do computational predictors say about CAP2 p.Ser134Leu (c.401C>T)?

AlphaMissense predicts likely pathogenic (score 0.8961) — an in-silico prediction, not a clinical call.

CAP2 p.Ser134Leu

c.401C>T · rs200559179 · VCV2285102

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8961 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8961	likely pathogenic · top 3% in CAP2
REVEL	0.614	indeterminate
SaProt	LLR -14.26	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.55 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00666% African / African-American · 5/75,046 alleles

Filtering AF 0.00402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00362%

Overall 0.00427% 69/1,614,172 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00666%	15,009
European (non-Finnish)	0.00508%	19,667
South Asian	0.0022%	45,542
Admixed American	0.00167%	60,022
Remaining individualsnot grpmax-eligible	0.0016%	62,512

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CAP2
Protein: p.Ser134Leu
Coding: c.401C>T
MANE Select: NM_019894 · reported on NM_006366
dbSNP: rs200559179
Type: single nucleotide variant
Location: chr6:17507269 (GRCh38)
Structure: AlphaFold pLDDT 88.01
Residue 134: a disulfide bond; the srcr domain

Full CAP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAP2 p.Arg17His Uncertain significance ★★ ⚠ same type
CAP2 p.His203Arg Uncertain significance ★★ ⚠ same type
TMPRSS4 p.Ala44Val Likely benign ★★ same type
CAP2 c.1003-5T>G Uncertain significance ★ same type
CAP2 p.Ala162Thr Uncertain significance ★ ⚠ same type
CAP2 p.Ala262Pro Uncertain significance ★ ⚠ same type
CAP2 p.Ala272Thr Uncertain significance ★ ⚠ same type
CAP2 p.Ala294Thr Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cap2-p-ser134leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown