Is CAPN3 p.Phe165= (c.495C>T) pathogenic?

CAPN3 p.Phe165= (c.495C>T) is classified Benign/Likely benign in CAPN3 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-03-01). Rare (popmax 0.923%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy type 2A.

What condition is associated with CAPN3 p.Phe165= (c.495C>T)?

CAPN3 p.Phe165= (c.495C>T) is associated with autosomal recessive limb-girdle muscular dystrophy type 2A (ClinVar).

How common is CAPN3 p.Phe165= (c.495C>T) in the general population?

CAPN3 p.Phe165= (c.495C>T) is rare (popmax 0.923%, nfe) (gnomAD).

CAPN3 p.Phe165=

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.495C>T · rs1801324 · VCV166785

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.923%, 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	Δ0.22	donor loss, 8 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.12	GERP -5.4, phastCons 0.93
Overall
CADD	8.503	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.923% European (non-Finnish) · 10,810/1,170,578 alleles

Filtering AF 0.909% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.903%

Overall 0.74% 11,866/1,603,796 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.923%	108
Remaining individualsnot grpmax-eligible	0.663%	151
Admixed American	0.538%	186
Amishnot grpmax-eligible	0.439%	228
Finnishnot grpmax-eligible	0.172%	582
Middle Eastern	0.166%	604
African / African-American	0.158%	634
Ashkenazi Jewishnot grpmax-eligible	0.135%	738
South Asian	0.0418%	2,391
East Asian	0.00223%	44,826

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.Phe165=
Coding: c.495C>T
MANE Select: NM_000070
dbSNP: rs1801324
Type: single nucleotide variant
Location: chr15:42386282 (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 165: the calpain catalytic domain; a β-strand

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.Phe165Leu 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-phe165 (accessed [today's date]).

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