Is CAPN1 p.Ala262Asp (c.785C>A) pathogenic?

CAPN1 p.Ala262Asp (c.785C>A) is classified Uncertain significance in CAPN1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-03-03). AlphaMissense: likely pathogenic (0.9083); Ultra-rare (popmax 0.0495%, mid).

How common is CAPN1 p.Ala262Asp (c.785C>A) in the general population?

CAPN1 p.Ala262Asp (c.785C>A) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about CAPN1 p.Ala262Asp (c.785C>A)?

AlphaMissense predicts likely pathogenic (score 0.9083) — an in-silico prediction, not a clinical call.

CAPN1 p.Ala262Asp

c.785C>A · rs192099450 · VCV2068941

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9083 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9083	likely pathogenic
REVEL	0.835	moderately pathogenic-leaning
SaProt	LLR -13.04	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 2.4, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 29 kb · p 4.3e-06 · regional, not allelic
Overall
CADD	26.1	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 0.0495% Middle Eastern · 3/6,060 alleles

Filtering AF 0.0423% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0411%

Overall 0.0364% 587/1,613,254 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,020
European (non-Finnish)	0.0455%	2,197
Remaining individualsnot grpmax-eligible	0.0352%	2,839
Admixed American	0.025%	3,996
African / African-American	0.0107%	9,381
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,586
Finnishnot grpmax-eligible	0.00156%	63,988

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: CAPN1
Protein: p.Ala262Asp
Coding: c.785C>A
MANE Select: NM_005186
dbSNP: rs192099450
Type: single nucleotide variant
Location: chr11:65187240 (GRCh38)
Gene constraint: LOEUF 0.977 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.03 · 5 PDB
Residue 262: the calpain catalytic domain

Full CAPN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN1 c.1605+5G>A Pathogenic/Likely pathogenic ★★ same type
CAPN1 c.267+2T>C Pathogenic/Likely pathogenic ★★ same type
CAPN1 c.338-1G>A Pathogenic ★★ same type
CAPN1 c.759+1G>A Pathogenic ★★ same type
CAPN1 c.843+1G>C Pathogenic/Likely pathogenic ★★ same type
CAPN1 c.929+2T>A Likely pathogenic ★★ same type
CAPN1 p.Arg285Ter Pathogenic/Likely pathogenic ★★ same type
CAPN1 p.Arg385Ter Pathogenic/Likely pathogenic ★★ 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/capn1-p-ala262asp (accessed [today's date]).

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