Is CAPS2 p.Val424Leu (c.1270G>C) pathogenic?

CAPS2 p.Val424Leu (c.1270G>C) is classified Uncertain significance in CAPS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-03). AlphaMissense: likely benign (0.2318); Rare (popmax 0.891%, afr).

How common is CAPS2 p.Val424Leu (c.1270G>C) in the general population?

CAPS2 p.Val424Leu (c.1270G>C) is rare (popmax 0.891%, afr) (gnomAD).

What do computational predictors say about CAPS2 p.Val424Leu (c.1270G>C)?

AlphaMissense predicts likely benign (score 0.2318) — an in-silico prediction, not a clinical call.

CAPS2 p.Val424Leu

c.1270G>C · VCV4219007

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2318 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.891%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.2318	likely benign
REVEL	0.027	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.4	GERP -1.4, phastCons 0.98
Overall
CADD	15.97	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V481L vs ClinVar V424L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.891% African / African-American · 668/75,004 alleles

Filtering AF 0.835% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.812%

Overall 0.0463% 746/1,612,236 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.891%	112
Remaining individualsnot grpmax-eligible	0.0705%	1,419
Admixed American	0.0384%	2,603
Middle Eastern	0.0167%	6,006
South Asian	0.0011%	90,838
European (non-Finnish)	0.000763%	131,046

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.Val424Leu
Coding: c.1270G>C
MANE Select: NM_017954 · reported on NM_001355024
Type: single nucleotide variant
Location: chr12:75289632 (GRCh38)
Structure: AlphaFold pLDDT 79.91
Residue 424: the c2 domain

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

Similar variants

CADPS2 c.3718-15A>C Benign ★★ same type
CADPS2 p.Ala298Thr Benign ★★ same type
CADPS2 p.Asp1088Asn Likely benign ★★ ⚠ same type
CADPS2 p.Glu1010Lys Benign ★★ same type
CADPS2 p.Leu154= Likely benign ★★ same type
CADPS2 p.Lys338= Benign ★★ same type
CADPS2 p.Met828Val Benign ★★ same type
CADPS2 p.Thr819= Benign ★★ 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-val424leu (accessed [today's date]).

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