Is CAPN12 p.Ala240Thr (c.718G>A) pathogenic?

CAPN12 p.Ala240Thr (c.718G>A) is classified Uncertain significance in CAPN12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-16). AlphaMissense: ambiguous (0.3894); Ultra-rare (popmax 0.034%, sas).

How common is CAPN12 p.Ala240Thr (c.718G>A) in the general population?

CAPN12 p.Ala240Thr (c.718G>A) is ultra-rare (popmax 0.034%, sas) (gnomAD).

What do computational predictors say about CAPN12 p.Ala240Thr (c.718G>A)?

AlphaMissense predicts ambiguous (score 0.3894) — an in-silico prediction, not a clinical call.

CAPN12 p.Ala240Thr

c.718G>A · VCV3995160

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3894 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.034%, sas)

Computational evidence

Protein change
AlphaMissense	0.3894	ambiguous
REVEL	0.307	indeterminate
SaProt	LLR -8.94	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP -0.13, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 13 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	25.0	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 0.034% South Asian · 30/88,280 alleles

Filtering AF 0.0244% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0211%

Overall 0.00315% 50/1,588,492 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.034%	2,943
Middle Eastern	0.019%	5,260
African / African-American	0.00808%	12,381
Finnishnot grpmax-eligible	0.00162%	61,654
European (non-Finnish)	0.00103%	97,192

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.Ala240Thr
Coding: c.718G>A
MANE Select: NM_144691
Type: single nucleotide variant
Location: chr19:38740062 (GRCh38)
Gene constraint: LOEUF 1.398 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.63
Residue 240: 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-ala240thr (accessed [today's date]).

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