Is CAPS2 p.Ile341Val (c.1021A>G) pathogenic?

CAPS2 p.Ile341Val (c.1021A>G) is classified Uncertain significance in CAPS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-20). AlphaMissense: likely benign (0.0695); Very rare (popmax 0.00334%, amr).

How common is CAPS2 p.Ile341Val (c.1021A>G) in the general population?

CAPS2 p.Ile341Val (c.1021A>G) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about CAPS2 p.Ile341Val (c.1021A>G)?

AlphaMissense predicts likely benign (score 0.0695) — an in-silico prediction, not a clinical call.

CAPS2 p.Ile341Val

c.1021A>G · VCV4648217

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0695 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0695	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	—	withheld · numbering disagrees past residue 8 · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.4	GERP 1.3, phastCons 1
Overall
CADD	8.882	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 is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM I398V vs ClinVar I341V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00334% Admixed American · 2/59,802 alleles

Filtering AF 0.000555% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000208%

Overall 0.000124% 2/1,609,596 alleles · very rare exomes 2/1,457,264 · genomes 0/152,332 · joint denominator

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: CAPS2
Protein: p.Ile341Val
Coding: c.1021A>G
MANE Select: NM_001355024
Type: single nucleotide variant
Location: chr12:75293277 (GRCh38)
Gene constraint: LOEUF 1.457 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.30

Full CAPS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPS2 p.Glu189= Benign ★★ same type
CAPS2 p.Ser52= Benign ★★ same type
CAPS2 c.1281+1G>C Uncertain significance ★ same type
CAPS2 c.177+130C>A Uncertain significance ★ ⚠ same type
CAPS2 c.177+142C>T Uncertain significance ★ ⚠ same type
CAPS2 c.177+156G>T Uncertain significance ★ ⚠ same type
CAPS2 c.354+1G>T Uncertain significance ★ same type
CAPS2 c.-1A>T 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/caps2-p-ile341val (accessed [today's date]).

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