Is CAPN3 p.Arg769= (c.2305C>A) pathogenic?

CAPN3 p.Arg769= (c.2305C>A) is classified Likely benign in CAPN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-14). Very rare (popmax 0.00195%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy type 2A.

What condition is associated with CAPN3 p.Arg769= (c.2305C>A)?

CAPN3 p.Arg769= (c.2305C>A) is associated with autosomal recessive limb-girdle muscular dystrophy type 2A (ClinVar).

How common is CAPN3 p.Arg769= (c.2305C>A) in the general population?

CAPN3 p.Arg769= (c.2305C>A) is very rare (popmax 0.00195%, nfe) (gnomAD).

CAPN3 p.Arg769=

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.2305C>A · rs868791726 · VCV1132756

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

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.
Splicing
SpliceAI	Δ0.44	donor gain · deltas
Pangolin	Δ0.63	gain · loss 0.07 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.3	GERP -0.053, phastCons 1
Overall
CADD	16.78	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00195% European (non-Finnish) · 23/1,179,964 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00155% 25/1,614,028 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00195%	51,303
Remaining individualsnot grpmax-eligible	0.0016%	62,490
African / African-American	0.00133%	74,944

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.Arg769=
Coding: c.2305C>A
MANE Select: NM_000070
dbSNP: rs868791726
Type: single nucleotide variant
Location: chr15:42410925 (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 769: the 'domain iv' region; a UniProt-annotated variant site (in lgmdr1); 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

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.Arg769Gln Pathogenic ★★★ same residue
CAPN3 p.Arg769Pro Likely pathogenic ★★★ same residue
CAPN3 p.Arg769Trp Pathogenic/Likely pathogenic ★★ same residue
CAPN3 p.Arg769Leu Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg769 (accessed [today's date]).

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