Is CAPN3 p.Glu667fs (c.1999dup) pathogenic?

CAPN3 p.Glu667fs (c.1999dup) is classified Pathogenic in CAPN3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-08-01). Very rare (popmax 0.00225%, eas); Associated with autosomal recessive limb-girdle muscular dystrophy type 2A.

What condition is associated with CAPN3 p.Glu667fs (c.1999dup)?

CAPN3 p.Glu667fs (c.1999dup) is associated with autosomal recessive limb-girdle muscular dystrophy type 2A (ClinVar).

How common is CAPN3 p.Glu667fs (c.1999dup) in the general population?

CAPN3 p.Glu667fs (c.1999dup) is very rare (popmax 0.00225%, eas) (gnomAD).

CAPN3 p.Glu667fs

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.1999dup · rs886044004 · VCV288777

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00225%, eas)

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 18 of 24
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00225% East Asian · 1/44,448 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000274% 4/1,460,480 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00225%	44,448
European (non-Finnish)	0.000255%	392,603

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.Glu667fs
Coding: c.1999dup
MANE Select: NM_000070
dbSNP: rs886044004
Type: Duplication
Location: chr15:42409791 (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 667: the 'domain iv' region; a binding site; the ef-hand 1 domain

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.Glu667Ter Pathogenic ★ same residue
CAPN3 p.Arg110fs Pathogenic ★★★ same condition
CAPN3 p.Asn760fs Pathogenic ★★★ same condition
CAPN3 p.Leu87fs Pathogenic ★★★ same condition
CAPN3 p.Tyr75fs Pathogenic ★★★ same condition
CAPN3 c.2115+1_2115+2dup Likely pathogenic ★★ same condition
CAPN3 p.Arg289fs Pathogenic ★★ same condition
CAPN3 p.Asn296delinsArgTer Likely 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-glu667fs (accessed [today's date]).

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