Is CAPN3 p.Arg489Trp (c.1465C>T) pathogenic?

CAPN3 p.Arg489Trp (c.1465C>T) is classified Pathogenic in CAPN3 (ClinVar, Expert panel, 13 submitters; last evaluated 2026-04-29). AlphaMissense: likely pathogenic (0.8946); Very rare (popmax 0.00446%, eas); Associated with autosomal recessive limb-girdle muscular dystrophy.

What condition is associated with CAPN3 p.Arg489Trp (c.1465C>T)?

CAPN3 p.Arg489Trp (c.1465C>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.Arg489Trp (c.1465C>T) in the general population?

CAPN3 p.Arg489Trp (c.1465C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about CAPN3 p.Arg489Trp (c.1465C>T)?

AlphaMissense predicts likely pathogenic (score 0.8946) — an in-silico prediction, not a clinical call.

CAPN3 p.Arg489Trp

c.1465C>T · rs863224957 · VCV217150

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 13 submitters

AlphaMissense

likely pathogenic

0.8946 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

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):

PM2_Supporting PM3_VeryStrong PP1 PP3 PP4

Curation rationale (ClinGen, verbatim)

The NM_000070.3: c.1465C>T variant in CAPN3 is a missense variant expected to cause the substitution of arginine at amino acid position 489 with tryptophan, p.(Arg489Trp). Across a selection of the available literature, this variant has been identified in at least nine unrelated individuals with features of LGMD (PMID: 18055493, 27066573, 27708273, 37526466, 15689361; LOVD CAPN3_000038). In one patient, it was confirmed in trans with a pathogenic variant (c.1715G>A p.(Arg572Gln), 1.0 pt, PMID: 27708273), and in six patients, it was reported in unconfirmed phase with a pathogenic variant (c.550del p.(Thr184ArgfsTer36), 0.5 pts x4, PMID: 18055493, 37526466, 15689361; c.2362_2363delinsTCATCT p.(Arg788SerfsTer14), 0.5 pts x2, PMID: 15689361) (PM3_Very Strong). At least one of these patients displayed progressive limb girdle muscle weakness (PP4). This variant has also been reported to segregate with autosomal recessive LGMD in one affected family member (PMID: 27708273; PP1). The upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.1 is 0.000054578 (51/1179994 European (non-Finnish) alleles), which is lower than the LGMD VCEP threshold of 0.0001, meeting the criteria for PM2_Supporting. The computational predictor REVEL also gives a score of 0.752, which is above the threshold of 0.7, 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 2.0.0; 04/29/2026): PM3_Very Strong, PP4, PP1, PM2_Supporting, PP3.

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

Computational evidence

Protein change
AlphaMissense	0.8946	likely pathogenic ✓ concordant with ClinVar
REVEL	0.752	pathogenic-leaning
SaProt	LLR -13.83	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 1.4	GERP -2.4, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.21 · regional, not allelic
Overall
CADD	31.0	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 0.00446% East Asian · 2/44,860 alleles

Filtering AF 0.00334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00302%

Overall 0.00359% 58/1,613,928 alleles · very rare exomes 57/1,461,836 · genomes 1/152,092 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,829
East Asiangrpmax	0.00446%	22,430
European (non-Finnish)	0.00432%	23,137
African / African-American	0.00134%	74,882
South Asian	0.0011%	91,074

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.Arg489Trp
Coding: c.1465C>T
MANE Select: NM_000070
dbSNP: rs863224957
Type: single nucleotide variant
Location: chr15:42401751 (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 489: 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.Arg489Gln 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
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-arg489trp (accessed [today's date]).

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