Is CAPN3 p.Phe604= (c.1812C>T) pathogenic?

CAPN3 p.Phe604= (c.1812C>T) is classified Likely benign in CAPN3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-20). Ultra-rare (popmax 0.0183%, amr); Associated with autosomal recessive limb-girdle muscular dystrophy type 2A.

What condition is associated with CAPN3 p.Phe604= (c.1812C>T)?

CAPN3 p.Phe604= (c.1812C>T) is associated with autosomal recessive limb-girdle muscular dystrophy type 2A (ClinVar).

How common is CAPN3 p.Phe604= (c.1812C>T) in the general population?

CAPN3 p.Phe604= (c.1812C>T) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

CAPN3 p.Phe604=

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.1812C>T · rs144383704 · VCV743177

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

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	Δ0.27	acceptor loss, 11 bp away · masked 0 · deltas
Pangolin	Δ0.28	loss · gain 0.05 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.7	GERP 1.6, phastCons 1
Overall
CADD	15.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0183% Admixed American · 11/59,960 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00786%

Overall 0.00242% 39/1,612,686 alleles · ultra-rare exomes 30/1,460,508 · genomes 9/152,178 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,451
East Asian	0.0134%	7,477
African / African-American	0.00401%	24,960
South Asian	0.0022%	45,509
European (non-Finnish)	0.00144%	69,365

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.Phe604=
Coding: c.1812C>T
MANE Select: NM_000070
dbSNP: rs144383704
Type: single nucleotide variant
Location: chr15:42408222 (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 604: the 'linker' region

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.Phe604del Uncertain significance ★ 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
CAPN3 p.Ala702Val 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-phe604 (accessed [today's date]).

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