Is CAP2 p.Ile364Thr (c.1091T>C) pathogenic?

CAP2 p.Ile364Thr (c.1091T>C) is classified Uncertain significance in CAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-11). AlphaMissense: likely pathogenic (0.7201); Very rare (popmax 0.000509%, nfe).

How common is CAP2 p.Ile364Thr (c.1091T>C) in the general population?

CAP2 p.Ile364Thr (c.1091T>C) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about CAP2 p.Ile364Thr (c.1091T>C)?

AlphaMissense predicts likely pathogenic (score 0.7201) — an in-silico prediction, not a clinical call.

CAP2 p.Ile364Thr

c.1091T>C · rs1762941382 · VCV1707067

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7201 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7201	likely pathogenic · top 9% in CAP2
REVEL	0.287	benign-leaning
SaProt	LLR -12.53	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 1
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000509% European (non-Finnish) · 6/1,179,680 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000411% 6/1,461,486 alleles · very rare

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.Ile364Thr
Coding: c.1091T>C
MANE Select: NM_019894 · reported on NM_006366
dbSNP: rs1762941382
Type: single nucleotide variant
Location: chr6:17542925 (GRCh38)
Structure: AlphaFold pLDDT 88.01
Residue 364: a disulfide bond; 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-ile364thr (accessed [today's date]).

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