Is CAPN3 p.Asp753= (c.2259C>T) pathogenic?

CAPN3 p.Asp753= (c.2259C>T) is classified Likely benign in CAPN3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-06-01). Very rare (popmax 0.00314%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy type 2A.

What condition is associated with CAPN3 p.Asp753= (c.2259C>T)?

CAPN3 p.Asp753= (c.2259C>T) is associated with autosomal recessive limb-girdle muscular dystrophy type 2A (ClinVar).

How common is CAPN3 p.Asp753= (c.2259C>T) in the general population?

CAPN3 p.Asp753= (c.2259C>T) is very rare (popmax 0.00314%, nfe) (gnomAD).

CAPN3 p.Asp753=

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.2259C>T · rs755010088 · VCV990251

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00314%, nfe)

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.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.78 · evaluated, not missing
Constraint at this position
Conservation	phyloP -8	GERP -5.4
Overall
CADD	4.703	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00314% European (non-Finnish) · 37/1,179,252 alleles

Filtering AF 0.00232% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.00267% 43/1,612,796 alleles · very rare exomes 42/1,460,926 · genomes 1/151,870 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,816
European (non-Finnish)grpmax	0.00314%	31,872
East Asian	0.00223%	44,874
Finnishnot grpmax-eligible	0.00156%	63,960
South Asian	0.0011%	91,010

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp753=
Coding: c.2259C>T
MANE Select: NM_000070
dbSNP: rs755010088
Type: single nucleotide variant
Location: chr15:42410662 (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 753: the 'domain iv' region; an α-helix; the ef-hand 3 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.Asp753Asn Likely benign ★★★ ⚠ same residue
CAPN3 p.Asp753del 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
CAPN3 c.1993-1G>A Pathogenic ★★★ same condition
CAPN3 c.499-1G>A 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-asp753 (accessed [today's date]).

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