Is CAPN3 p.Arg490Trp (c.1468C>T) pathogenic?

CAPN3 p.Arg490Trp (c.1468C>T) is classified Pathogenic in CAPN3 (ClinVar, Expert panel, 25 submitters; last evaluated 2025-01-09). AlphaMissense: likely pathogenic (0.9607); Ultra-rare (popmax 0.0283%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy.

What condition is associated with CAPN3 p.Arg490Trp (c.1468C>T)?

CAPN3 p.Arg490Trp (c.1468C>T) is associated with autosomal recessive limb-girdle muscular dystrophy, autosomal recessive limb-girdle muscular dystrophy type 2A, muscular dystrophy, limb-girdle, autosomal dominant 4 (ClinVar).

How common is CAPN3 p.Arg490Trp (c.1468C>T) in the general population?

CAPN3 p.Arg490Trp (c.1468C>T) is ultra-rare (popmax 0.0283%, nfe) (gnomAD).

What do computational predictors say about CAPN3 p.Arg490Trp (c.1468C>T)?

AlphaMissense predicts likely pathogenic (score 0.9607) — an in-silico prediction, not a clinical call.

CAPN3 p.Arg490Trp

c.1468C>T · rs141656719 · VCV166790

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 25 submitters

AlphaMissense

likely pathogenic

0.9607 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0283%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive limb-girdle muscular dystrophy

ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP

Pathogenic for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):

PP4_Moderate PM3_VeryStrong PP3

Curation rationale (ClinGen, verbatim)

The NM_000070.3: c.1468C>T variant in CAPN3 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 490 (p.Arg490Trp). This variant has been detected in at least 18 individuals with limb girdle muscular dystrophy (PMID: 18055493, 10330340, 25214167, 25135358, 26632398, 12461690, 17994539), including in a homozygous state in at least two cases (1.0 pt; PMID: 18055493), confirmed in trans with a pathogenic variant in one case (c.550del p.(Thr184ArgfsTer36), 1.0 pt, PMID: 17994539), and in unknown phase with a pathogenic variant in four cases c.550del p.(Thr184ArgfsTer36), 1.0 pt, PMID: 25135358; c.2279dup p.(Asn760LysfsTer5), 0.5 pts, PMID: 18055493; c.2242C>T p.(Arg748Ter), 0.5 pts, PMID: 25214167) (PM3_Very Strong). At least one patient with this variant was clinically suspected to have limb girdle muscular dystrophy and displayed reduced calpain-3 protein expression, which is specific for CAPN3-related LGMD (PP4_Moderate; PMID: 17994539). The highest population minor allele frequency of this variant is 0.0004598 (4/8700 genome alleles) in the African/African American population in gnomAD v2.1.1, which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.84, which is above the VCEP threshold of 0.70, evidence that correlates with impact to CAPN3 function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PM3_Very Strong, PP4_Moderate, PP3.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9607	likely pathogenic ✓ concordant with ClinVar
REVEL	0.839	moderately pathogenic-leaning
SaProt	LLR -15.89	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.68	GERP -5.6, phastCons 0.96
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.21 · regional, not allelic
Overall
CADD	25.4	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 0.0283% European (non-Finnish) · 334/1,179,974 alleles

Filtering AF 0.0258% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0248%

Overall 0.0227% 367/1,613,988 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0283%	3,533
African / African-American	0.0213%	4,687
Admixed American	0.01%	10,001
East Asian	0.00669%	14,944
Remaining individualsnot grpmax-eligible	0.0064%	15,627
South Asian	0.00329%	30,358
Finnishnot grpmax-eligible	0.00156%	64,028

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.Arg490Trp
Coding: c.1468C>T
MANE Select: NM_000070
dbSNP: rs141656719
Type: single nucleotide variant
Location: chr15:42401754 (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 490: the 'domain iii' region; a UniProt-annotated variant site (in lgmdr1)

Full CAPN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive limb-girdle muscular dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2A muscular dystrophy, limb-girdle, autosomal dominant 4

Similar variants

CAPN3 p.Arg490Gln Pathogenic ★★★ same residue
CAPN3 p.Arg490fs Pathogenic/Likely pathogenic ★★ 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-arg490trp (accessed [today's date]).

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