Is CAPN3 p.Ala385Val (c.1154C>T) pathogenic?

CAPN3 p.Ala385Val (c.1154C>T) is classified Uncertain significance in CAPN3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-03-12). AlphaMissense: likely benign (0.0845); Very rare (popmax 0.000274%); Associated with Inborn genetic diseases.

What condition is associated with CAPN3 p.Ala385Val (c.1154C>T)?

CAPN3 p.Ala385Val (c.1154C>T) is associated with Inborn genetic diseases, autosomal recessive limb-girdle muscular dystrophy type 2A (ClinVar).

How common is CAPN3 p.Ala385Val (c.1154C>T) in the general population?

CAPN3 p.Ala385Val (c.1154C>T) is very rare (popmax 0.000274%) (gnomAD).

What do computational predictors say about CAPN3 p.Ala385Val (c.1154C>T)?

AlphaMissense predicts likely benign (score 0.0845) — an in-silico prediction, not a clinical call.

CAPN3 p.Ala385Val

c.1154C>T · rs934135114 · VCV1410463

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0845 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000274%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0845	likely benign
REVEL	0.237	benign-leaning
SaProt	LLR -6.00	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -0.15, phastCons 0.97
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.21 · regional, not allelic
Overall
CADD	17.36	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000274%

Overall 0.000274% 4/1,461,696 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.Ala385Val
Coding: c.1154C>T
MANE Select: NM_000070
dbSNP: rs934135114
Type: single nucleotide variant
Location: chr15:42396838 (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 385: the calpain catalytic domain; an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2A

Similar variants

CAPN3 p.Ala385= Likely benign ★ 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-ala385val (accessed [today's date]).

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