Is CAPN3 p.Val98Ile (c.292G>A) pathogenic?

CAPN3 p.Val98Ile (c.292G>A) is classified Uncertain significance in CAPN3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-07-23). AlphaMissense: likely benign (0.0676); Ultra-rare (popmax 0.0166%, nfe); Associated with muscular dystrophy, limb-girdle, autosomal dominant 4.

What condition is associated with CAPN3 p.Val98Ile (c.292G>A)?

CAPN3 p.Val98Ile (c.292G>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.Val98Ile (c.292G>A) in the general population?

CAPN3 p.Val98Ile (c.292G>A) is ultra-rare (popmax 0.0166%, nfe) (gnomAD).

What do computational predictors say about CAPN3 p.Val98Ile (c.292G>A)?

AlphaMissense predicts likely benign (score 0.0676) — an in-silico prediction, not a clinical call.

CAPN3 p.Val98Ile

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.292G>A · rs368585092 · VCV284578

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0676 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

muscular dystrophy, limb-girdle, autosomal dominant 4

Computational evidence

Protein change
AlphaMissense	0.0676	likely benign
REVEL	0.235	benign-leaning
SaProt	LLR -6.10	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.42	GERP -5.1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.21 · regional, not allelic
Overall
CADD	0.649	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% European (non-Finnish) · 196/1,180,020 alleles

Filtering AF 0.0147% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.014%

Overall 0.0131% 211/1,614,186 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0166%	6,021
Remaining individualsnot grpmax-eligible	0.0064%	15,625
South Asian	0.00549%	18,217
African / African-American	0.00533%	18,763
Admixed American	0.00333%	30,016

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.Val98Ile
Coding: c.292G>A
MANE Select: NM_000070
dbSNP: rs368585092
Type: single nucleotide variant
Location: chr15:42360097 (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 98: the calpain catalytic domain; a β-strand; a UniProt-annotated variant site (in lgmdr1)

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.Val98= Likely benign ★ same residue
CAPN3 p.Val98Phe Uncertain significance ⚠ same residue
CAPN3 p.Val98fs 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-val98ile (accessed [today's date]).

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