Is CAPN12 p.Val153Met (c.457G>A) pathogenic?

CAPN12 p.Val153Met (c.457G>A) is classified Uncertain significance in CAPN12 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-28). AlphaMissense: ambiguous (0.4451); Very rare (popmax 0.00668%, eas).

How common is CAPN12 p.Val153Met (c.457G>A) in the general population?

CAPN12 p.Val153Met (c.457G>A) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about CAPN12 p.Val153Met (c.457G>A)?

AlphaMissense predicts ambiguous (score 0.4451) — an in-silico prediction, not a clinical call.

CAPN12 p.Val153Met

c.457G>A · VCV3827210

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4451 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4451	ambiguous
REVEL	0.768	pathogenic-leaning
SaProt	LLR -9.66	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2.7, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 13 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	27.5	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 0.00668% East Asian · 3/44,886 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000753% 11/1,461,726 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,962
European (non-Finnish)	0.000678%	147,503

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: CAPN12
Protein: p.Val153Met
Coding: c.457G>A
MANE Select: NM_144691
Type: single nucleotide variant
Location: chr19:38741880 (GRCh38)
Gene constraint: LOEUF 1.398 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.63
Residue 153: the calpain catalytic domain

Full CAPN12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN12 c.1362+80A>G Benign ★★ same type
CAPN12 c.1374+85A>C Benign ★★ same type
CAPN12 c.1583+12G>A Benign ★★ same type
CAPN12 c.1584-39C>T Benign ★★ same type
CAPN12 c.1686+152A>G Benign ★★ same type
CAPN12 c.1745-17C>T Benign ★★ same type
CAPN12 c.1815+25G>A Benign ★★ same type
CAPN12 c.1815+57C>T 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/capn12-p-val153met (accessed [today's date]).

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