Is CAPN3 p.Asp452His (c.1354G>C) pathogenic?

CAPN3 p.Asp452His (c.1354G>C) is classified Likely pathogenic in CAPN3 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-06-15). AlphaMissense: likely pathogenic (0.7015); Absent from gnomAD v4.1; Associated with muscular dystrophy, limb-girdle, autosomal dominant 4.

What condition is associated with CAPN3 p.Asp452His (c.1354G>C)?

CAPN3 p.Asp452His (c.1354G>C) is associated with muscular dystrophy, limb-girdle, autosomal dominant 4, autosomal recessive limb-girdle muscular dystrophy type 2A (ClinVar).

How common is CAPN3 p.Asp452His (c.1354G>C) in the general population?

CAPN3 p.Asp452His (c.1354G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CAPN3 p.Asp452His (c.1354G>C)?

AlphaMissense predicts likely pathogenic (score 0.7015) — an in-silico prediction, not a clinical call.

CAPN3 p.Asp452His

Q: How is Calpain-3-related limb-girdle muscular dystrophy D4 inherited?

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

c.1354G>C · rs727503838 · VCV553345

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7015 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

muscular dystrophy, limb-girdle, autosomal dominant 4

Computational evidence

Protein change
AlphaMissense	0.7015	likely pathogenic ✓ concordant with ClinVar
REVEL	0.875	moderately pathogenic-leaning
SaProt	LLR -7.59	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.99	donor loss · deltas
Pangolin	Δ0.84	loss · gain 0.69 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.21 · regional, not allelic
Overall
CADD	36.0	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

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.Asp452His
Coding: c.1354G>C
MANE Select: NM_000070
dbSNP: rs727503838
Type: single nucleotide variant
Location: chr15:42399652 (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 452: the 'domain iii' region

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

Disease context

muscular dystrophy, limb-girdle, autosomal dominant 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Calpain-3-related limb-girdle muscular dystrophy D4 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

CAPN3 p.Asp452Tyr Uncertain significance ★★★ ⚠ same residue
CAPN3 p.Asp452Gly Uncertain significance ★★ ⚠ 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-asp452his (accessed [today's date]).

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