Is CAPN3 p.Gln545Ter (c.1633C>T) pathogenic?

CAPN3 p.Gln545Ter (c.1633C>T) is classified Likely pathogenic in CAPN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-23). Very rare (popmax 8.47e-05%, nfe); Associated with muscular dystrophy, limb-girdle, autosomal dominant 4.

What condition is associated with CAPN3 p.Gln545Ter (c.1633C>T)?

CAPN3 p.Gln545Ter (c.1633C>T) is associated with muscular dystrophy, limb-girdle, autosomal dominant 4, autosomal recessive limb-girdle muscular dystrophy type 2A (ClinVar).

How common is CAPN3 p.Gln545Ter (c.1633C>T) in the general population?

CAPN3 p.Gln545Ter (c.1633C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

CAPN3 p.Gln545Ter

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.1633C>T · VCV3577108

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

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

Conditions

muscular dystrophy, limb-girdle, autosomal dominant 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 13 of 24
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -0.15, phastCons 0.96
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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,994 alleles

Overall 0.000657% 1/152,232 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.Gln545Ter
Coding: c.1633C>T
MANE Select: NM_000070
Type: single nucleotide variant
Location: chr15:42402890 (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 545: 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 c.1115+5G>C Pathogenic ★★★ same condition
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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
CAPN3 p.Ala798Glu 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-gln545ter (accessed [today's date]).

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