Is CAPN3 p.Asp780Ter (c.2337dup) pathogenic?

CAPN3 p.Asp780Ter (c.2337dup) is classified Pathogenic/Likely pathogenic in CAPN3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-05). Very rare (popmax 0.00267%, afr); Associated with autosomal recessive limb-girdle muscular dystrophy type 2A.

What condition is associated with CAPN3 p.Asp780Ter (c.2337dup)?

CAPN3 p.Asp780Ter (c.2337dup) is associated with autosomal recessive limb-girdle muscular dystrophy type 2A, muscular dystrophy, limb-girdle, autosomal dominant 4 (ClinVar).

How common is CAPN3 p.Asp780Ter (c.2337dup) in the general population?

CAPN3 p.Asp780Ter (c.2337dup) is very rare (popmax 0.00267%, afr) (gnomAD).

CAPN3 p.Asp780Ter

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.2337dup · rs1447774727 · VCV558697

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

Rare

very rare (popmax 0.00267%, afr)

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	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 22 of 24
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4	GERP 1.1, phastCons 1
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 0.00267% African / African-American · 2/74,942 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00131% 2/152,250 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.Asp780Ter
Coding: c.2337dup
MANE Select: NM_000070
dbSNP: rs1447774727
Type: Duplication
Location: chr15:42410954 (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 780: the 'domain iv' region; an α-helix

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.Asp780fs Likely pathogenic ★★ same residue
CAPN3 p.Asp780His Pathogenic ★★ same residue
CAPN3 p.Asp780= Likely benign ★ 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

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-asp780ter (accessed [today's date]).

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