Is CAPN14 p.Val474Met (c.1420G>A) pathogenic?

CAPN14 p.Val474Met (c.1420G>A) is classified Uncertain significance in CAPN14 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-21). AlphaMissense: likely benign (0.3071); Very rare (popmax 0.00567%, nfe).

How common is CAPN14 p.Val474Met (c.1420G>A) in the general population?

CAPN14 p.Val474Met (c.1420G>A) is very rare (popmax 0.00567%, nfe) (gnomAD).

What do computational predictors say about CAPN14 p.Val474Met (c.1420G>A)?

AlphaMissense predicts likely benign (score 0.3071) — an in-silico prediction, not a clinical call.

CAPN14 p.Val474Met

c.1420G>A · VCV4648097

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3071 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00567%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3071	likely benign
REVEL	0.543	indeterminate
SaProt	LLR -10.27	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.74	GERP -1.3
Regional constraint	o/e 1.01	unconstrained · MANE · 31 kb · p 0.76 · regional, not allelic
Overall
CADD	16.82	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 0.00567% European (non-Finnish) · 65/1,146,902 alleles

Filtering AF 0.00456% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00415%

Overall 0.00458% 71/1,551,624 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00567%	17,645
South Asian	0.00476%	21,013
Remaining individualsnot grpmax-eligible	0.00166%	60,114
African / African-American	0.00137%	73,182

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: CAPN14
Protein: p.Val474Met
Coding: c.1420G>A
MANE Select: NM_001145122
Type: single nucleotide variant
Location: chr2:31189346 (GRCh38)
Gene constraint: LOEUF 1.109 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.02
Residue 474: the 'domain iii' region

Full CAPN14 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN14 p.Leu185= Benign ★★ same type
CAPN14 p.Ala183Thr Uncertain significance ★ ⚠ same type
CAPN14 p.Ala255Thr Uncertain significance ★ ⚠ same type
CAPN14 p.Ala35Thr Uncertain significance ★ ⚠ same type
CAPN14 p.Ala51Thr Uncertain significance ★ ⚠ same type
CAPN14 p.Ala613Val Uncertain significance ★ ⚠ same type
CAPN14 p.Arg119Gln Uncertain significance ★ ⚠ same type
CAPN14 p.Arg119Trp 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/capn14-p-val474met (accessed [today's date]).

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