Is CAPN12 p.Arg492Ser (c.1474C>A) pathogenic?

CAPN12 p.Arg492Ser (c.1474C>A) is classified Uncertain significance in CAPN12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-22). AlphaMissense: likely pathogenic (0.8908); Ultra-rare (popmax 0.0165%, eas).

How common is CAPN12 p.Arg492Ser (c.1474C>A) in the general population?

CAPN12 p.Arg492Ser (c.1474C>A) is ultra-rare (popmax 0.0165%, eas) (gnomAD).

What do computational predictors say about CAPN12 p.Arg492Ser (c.1474C>A)?

AlphaMissense predicts likely pathogenic (score 0.8908) — an in-silico prediction, not a clinical call.

CAPN12 p.Arg492Ser

c.1474C>A · VCV3827196

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8908 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8908	likely pathogenic · top 9% in CAPN12
REVEL	0.616	indeterminate
SaProt	LLR -11.91	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.35	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 13 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% East Asian · 6/36,404 alleles

Filtering AF 0.0071% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00487%

Overall 0.000933% 14/1,500,732 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0165%	6,067
Remaining individualsnot grpmax-eligible	0.0121%	8,295
European (non-Finnish)	8.85e-05%	1,130,162

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.Arg492Ser
Coding: c.1474C>A
MANE Select: NM_144691
Type: single nucleotide variant
Location: chr19:38736219 (GRCh38)
Gene constraint: LOEUF 1.398 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.63
Residue 492: the 'domain iii' region

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-arg492ser (accessed [today's date]).

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