Is CAPN3 p.Arg147Gln (c.440G>A) pathogenic?

CAPN3 p.Arg147Gln (c.440G>A) is classified Uncertain significance in CAPN3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-01-13). AlphaMissense: ambiguous (0.3758); Very rare (popmax 0.00668%, eas); Associated with muscular dystrophy, limb-girdle, autosomal dominant 4.

What condition is associated with CAPN3 p.Arg147Gln (c.440G>A)?

CAPN3 p.Arg147Gln (c.440G>A) is associated with muscular dystrophy, limb-girdle, autosomal dominant 4, autosomal recessive limb-girdle muscular dystrophy type 2A (ClinVar).

How common is CAPN3 p.Arg147Gln (c.440G>A) in the general population?

CAPN3 p.Arg147Gln (c.440G>A) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about CAPN3 p.Arg147Gln (c.440G>A)?

AlphaMissense predicts ambiguous (score 0.3758) — an in-silico prediction, not a clinical call.

CAPN3 p.Arg147Gln

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.440G>A · rs139671324 · VCV552291

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.3758 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

muscular dystrophy, limb-girdle, autosomal dominant 4

Computational evidence

Protein change
AlphaMissense	0.3758	ambiguous
REVEL	0.745	pathogenic-leaning
SaProt	LLR -10.26	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.21 · regional, not allelic
Overall
CADD	33.0	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 0.00668% East Asian · 3/44,878 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00223% 36/1,613,954 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,959
African / African-American	0.00401%	24,967
European (non-Finnish)	0.00246%	40,689
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Arg147Gln
Coding: c.440G>A
MANE Select: NM_000070
dbSNP: rs139671324
Type: single nucleotide variant
Location: chr15:42386227 (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 147: the calpain catalytic domain; 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

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.Arg147Ter Pathogenic ★★ same residue
CAPN3 p.Arg147= Uncertain significance ★ same residue
CAPN3 p.Arg147Leu 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

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-arg147gln (accessed [today's date]).

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