Is CAPN3 p.Arg769Trp (c.2305C>T) pathogenic?

CAPN3 p.Arg769Trp (c.2305C>T) is classified Pathogenic/Likely pathogenic in CAPN3 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-01-29). AlphaMissense: likely pathogenic (0.9839); Very rare (popmax 0.00446%, eas); Associated with muscular dystrophy, limb-girdle, autosomal dominant 4.

What condition is associated with CAPN3 p.Arg769Trp (c.2305C>T)?

CAPN3 p.Arg769Trp (c.2305C>T) is associated with muscular dystrophy, limb-girdle, autosomal dominant 4, autosomal recessive limb-girdle muscular dystrophy type 2A, autosomal recessive limb-girdle muscular dystrophy (ClinVar).

How common is CAPN3 p.Arg769Trp (c.2305C>T) in the general population?

CAPN3 p.Arg769Trp (c.2305C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about CAPN3 p.Arg769Trp (c.2305C>T)?

AlphaMissense predicts likely pathogenic (score 0.9839) — an in-silico prediction, not a clinical call.

CAPN3 p.Arg769Trp

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.2305C>T · rs868791726 · VCV282411

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

AlphaMissense

likely pathogenic

0.9839 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

muscular dystrophy, limb-girdle, autosomal dominant 4

Computational evidence

Protein change
AlphaMissense	0.9839	likely pathogenic ✓ concordant with ClinVar
REVEL	0.958	strongly pathogenic-leaning
SaProt	LLR -14.82	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.44 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.3	GERP -0.053, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.21 · regional, not allelic
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,888 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00164% 24/1,461,784 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,444
African / African-American	0.004%	25,022
Admixed American	0.00167%	60,028
Remaining individualsnot grpmax-eligible	0.0016%	62,512
European (non-Finnish)	0.00144%	69,409

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.Arg769Trp
Coding: c.2305C>T
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

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 autosomal recessive limb-girdle muscular dystrophy

For Calpain-3-related limb-girdle muscular dystrophy D4 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

CAPN3 p.Arg769Gln Pathogenic ★★★ same residue
CAPN3 p.Arg769Pro Likely pathogenic ★★★ same residue
CAPN3 p.Arg769Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CAPN3 p.Arg769= Likely benign ★ 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-arg769trp (accessed [today's date]).

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