Is CAPN3 p.Arg541Trp (c.1621C>T) pathogenic?

CAPN3 p.Arg541Trp (c.1621C>T) is classified Pathogenic in CAPN3 (ClinVar, Expert panel, 17 submitters; last evaluated 2025-12-29). AlphaMissense: likely pathogenic (0.9844); Very rare (popmax 0.00445%, eas); Associated with autosomal recessive limb-girdle muscular dystrophy.

What condition is associated with CAPN3 p.Arg541Trp (c.1621C>T)?

CAPN3 p.Arg541Trp (c.1621C>T) is associated with autosomal recessive limb-girdle muscular dystrophy, type 2 diabetes mellitus, autosomal recessive limb-girdle muscular dystrophy type 2A (ClinVar).

How common is CAPN3 p.Arg541Trp (c.1621C>T) in the general population?

CAPN3 p.Arg541Trp (c.1621C>T) is very rare (popmax 0.00445%, eas) (gnomAD).

What do computational predictors say about CAPN3 p.Arg541Trp (c.1621C>T)?

AlphaMissense predicts likely pathogenic (score 0.9844) — an in-silico prediction, not a clinical call.

CAPN3 p.Arg541Trp

c.1621C>T · rs142004418 · VCV498267

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 17 submitters

AlphaMissense

likely pathogenic

0.9844 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, 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_Moderate PP3 PP4

Curation rationale (ClinGen, verbatim)

The NM_000070.3: c.1621C>T variant in CAPN3 is a missense variant predicted to cause the substitution of tryptophan for arginine at position 541, p.(Arg541Trp). Across a selection of the available literature, this variant has been reported in at least 11 unrelated patients with features of LGMD (PMID: 19556129, 18854869, 32576226, 30919934, 25214167, 16100770, 36575883, 31066050), including in a homozygous state in two unrelated probands without reported consanguinity (0.5 pts x2; PMID: 31066050, 30919934), confirmed in trans with a pathogenic variant in three probands (c.701G>A p.(Gly234Glu), 1.0 pt, PMID: 3657588; c.550del p.(Thr184ArgfsTer36), 1.0 pt, PMID: 16100770; c.598_612del p.(Phe200_Leu204del), 1.0 pt, PMID: 16100770), and in unconfirmed phase with a pathogenic variant in two probands (c.550del p.(Thr184ArgfsTer36), 0.5 pts, PMID: 16100770; c.598_612del p.(Phe200_Leu204del), 0.5 pts, PMID: 18854869) (PM3_Very Strong). At least one patient with this variant and a second presumed diagnostic CAPN3 allele displayed progressive limb girdle muscle weakness (PP4). In addition, two affected family members of a homozygous proband were also shown to be homozygous for this variant (PMID: 30919934; PP1_Moderate). The highest population variant allele frequency in gnomAD v4.1.0 for is 0.00004455 (2/44898 East Asian chromosomes), which is is lower than the LGMD VCEP threshold (<0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.896, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function. 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; 12/29/2025): PM3_Very Strong, PP4, PP1_Moderate, PM2_Supporting, PP3.

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

Computational evidence

Protein change
AlphaMissense	0.9844	likely pathogenic ✓ concordant with ClinVar
REVEL	0.896	moderately pathogenic-leaning
SaProt	LLR -14.31	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 2.6	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 0.00445% East Asian · 2/44,898 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.0018% 29/1,613,992 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,449
Remaining individualsnot grpmax-eligible	0.0032%	31,244
South Asian	0.0022%	45,541
European (non-Finnish)	0.00186%	53,635
Admixed American	0.00167%	60,000

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.Arg541Trp
Coding: c.1621C>T
MANE Select: NM_000070
dbSNP: rs142004418
Type: single nucleotide variant
Location: chr15:42402878 (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 541: 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: type 2 diabetes mellitus autosomal recessive limb-girdle muscular dystrophy type 2A muscular dystrophy, limb-girdle, autosomal dominant 4

Similar variants

CAPN3 p.Arg541Gln Pathogenic ★★★ same residue
CAPN3 p.Arg541Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
CAPN3 p.Arg541Pro 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

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-arg541trp (accessed [today's date]).

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