Is CAP2 p.Pro235Ala (c.703C>G) pathogenic?

CAP2 p.Pro235Ala (c.703C>G) is classified Uncertain significance in CAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-20). AlphaMissense: likely benign (0.0813); Ultra-rare (popmax 0.0658%, mid).

How common is CAP2 p.Pro235Ala (c.703C>G) in the general population?

CAP2 p.Pro235Ala (c.703C>G) is ultra-rare (popmax 0.0658%, mid) (gnomAD).

What do computational predictors say about CAP2 p.Pro235Ala (c.703C>G)?

AlphaMissense predicts likely benign (score 0.0813) — an in-silico prediction, not a clinical call.

CAP2 p.Pro235Ala

c.703C>G · VCV3263134

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0813 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0658%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0813	likely benign
REVEL	0.227	benign-leaning
SaProt	LLR -9.17	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 0.8, phastCons 1
Overall
CADD	21.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0658% Middle Eastern · 4/6,082 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0171%

Overall 0.00626% 101/1,613,882 alleles · ultra-rare exomes 99/1,461,692 · genomes 2/152,190 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0658%	1,521
South Asian	0.0285%	3,503
European (non-Finnish)	0.00568%	17,610
Remaining individualsnot grpmax-eligible	0.0048%	20,825
Admixed American	0.00167%	59,998

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.Pro235Ala
Coding: c.703C>G
MANE Select: NM_006366
Type: single nucleotide variant
Location: chr6:17539335 (GRCh38)
Structure: AlphaFold pLDDT 88.01
Residue 235: the peptidase s1 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-pro235ala (accessed [today's date]).

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