Is CAPN3 p.Tyr185Asp (c.553T>G) pathogenic?

CAPN3 p.Tyr185Asp (c.553T>G) is classified Uncertain significance in CAPN3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-30). AlphaMissense: likely pathogenic (0.7204); Absent from gnomAD v4.1; Associated with autosomal recessive limb-girdle muscular dystrophy type 2A.

What condition is associated with CAPN3 p.Tyr185Asp (c.553T>G)?

CAPN3 p.Tyr185Asp (c.553T>G) is associated with autosomal recessive limb-girdle muscular dystrophy type 2A (ClinVar).

How common is CAPN3 p.Tyr185Asp (c.553T>G) in the general population?

CAPN3 p.Tyr185Asp (c.553T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CAPN3 p.Tyr185Asp (c.553T>G)?

AlphaMissense predicts likely pathogenic (score 0.7204) — an in-silico prediction, not a clinical call.

CAPN3 p.Tyr185Asp

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.553T>G · rs1566975069 · VCV598304

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7204 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2A

Computational evidence

Protein change
AlphaMissense	0.7204	likely pathogenic
REVEL	0.718	pathogenic-leaning
SaProt	LLR -11.23	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 6.2	GERP 0.49, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.21 · regional, not allelic
Overall
CADD	27.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CAPN3
Protein: p.Tyr185Asp
Coding: c.553T>G
MANE Select: NM_000070
dbSNP: rs1566975069
Type: single nucleotide variant
Location: chr15:42387807 (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 185: the calpain catalytic domain; a β-strand

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.Tyr185Ter Likely pathogenic ★ same residue
CAPN3 p.Tyr185= 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

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-tyr185asp (accessed [today's date]).

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