Is CAPN3 p.Ala497Pro (c.1489G>C) pathogenic?

CAPN3 p.Ala497Pro (c.1489G>C) is classified Uncertain significance in CAPN3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-07). AlphaMissense: likely pathogenic (0.8023); Very rare (popmax 8.47e-05%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy type 2A.

What condition is associated with CAPN3 p.Ala497Pro (c.1489G>C)?

CAPN3 p.Ala497Pro (c.1489G>C) is associated with autosomal recessive limb-girdle muscular dystrophy type 2A (ClinVar).

How common is CAPN3 p.Ala497Pro (c.1489G>C) in the general population?

CAPN3 p.Ala497Pro (c.1489G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CAPN3 p.Ala497Pro (c.1489G>C)?

AlphaMissense predicts likely pathogenic (score 0.8023) — an in-silico prediction, not a clinical call.

CAPN3 p.Ala497Pro

Q: How is Calpain-3-related limb-girdle muscular dystrophy R1 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1489G>C · rs764770392 · VCV2688717

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8023 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2A

Computational evidence

Protein change
AlphaMissense	0.8023	likely pathogenic
REVEL	0.428	indeterminate
SaProt	LLR -8.17	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.21 · regional, not allelic
Overall
CADD	24.7	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 8.47e-05% European (non-Finnish) · 1/1,179,982 alleles

Overall 0.000657% 1/152,198 alleles · very rare

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: CAPN3
Protein: p.Ala497Pro
Coding: c.1489G>C
MANE Select: NM_000070
dbSNP: rs764770392
Type: single nucleotide variant
Location: chr15:42401775 (GRCh38)
Gene constraint: LOEUF 0.896 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 79.18 · 5 PDB
Residue 497: the 'domain iii' region

Full CAPN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive limb-girdle muscular dystrophy type 2A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Calpain-3-related limb-girdle muscular dystrophy R1 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CAPN3 p.Ala497fs Pathogenic/Likely pathogenic ★★ same residue
CAPN3 c.1115+5G>C Pathogenic ★★★ same condition
CAPN3 c.1194-2A>G Pathogenic ★★★ same condition
CAPN3 c.1194-9A>G Pathogenic ★★★ same condition
CAPN3 c.1746-20C>G Pathogenic ★★★ same condition
CAPN3 c.1993-1G>A Pathogenic ★★★ same condition
CAPN3 c.499-1G>A Pathogenic ★★★ same condition
CAPN3 p.Ala702Val Pathogenic ★★★ same condition

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/capn3-p-ala497pro (accessed [today's date]).

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