Is CAPN3 p.Gln635Ter (c.1903C>T) pathogenic?

CAPN3 p.Gln635Ter (c.1903C>T) is classified Pathogenic/Likely pathogenic in CAPN3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-19). Absent from gnomAD v4.1; Associated with autosomal recessive limb-girdle muscular dystrophy type 2A.

What condition is associated with CAPN3 p.Gln635Ter (c.1903C>T)?

CAPN3 p.Gln635Ter (c.1903C>T) is associated with autosomal recessive limb-girdle muscular dystrophy type 2A, muscular dystrophy, limb-girdle, autosomal dominant 4 (ClinVar).

How common is CAPN3 p.Gln635Ter (c.1903C>T) in the general population?

CAPN3 p.Gln635Ter (c.1903C>T) is absent from gnomAD v4.1 (gnomAD).

CAPN3 p.Gln635Ter

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.1903C>T · rs768437317 · VCV2096492

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 16 of 24
Splicing
SpliceAI	Δ0.48	donor loss · deltas
Pangolin	Δ0.46	loss · gain 0.16 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2	GERP -2.1, phastCons 0.67
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

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.Gln635Ter
Coding: c.1903C>T
MANE Select: NM_000070
dbSNP: rs768437317
Type: single nucleotide variant
Location: chr15:42408313 (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 635: the 'linker' region; the 'disordered' 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

Also linked: muscular dystrophy, limb-girdle, autosomal dominant 4

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.Gln635Arg Uncertain significance ★ ⚠ same residue
CAPN3 p.Gln635Glu 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-gln635ter (accessed [today's date]).

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