Is CAPN3 p.Leu144Phe (c.430C>T) pathogenic?

CAPN3 p.Leu144Phe (c.430C>T) is classified Uncertain significance in CAPN3 (ClinVar, Single submitter, 1 submitter). AlphaMissense: ambiguous (0.484); Very rare (popmax 0.0011%, sas); Associated with muscular dystrophy, limb-girdle, autosomal dominant 4.

What condition is associated with CAPN3 p.Leu144Phe (c.430C>T)?

CAPN3 p.Leu144Phe (c.430C>T) is associated with muscular dystrophy, limb-girdle, autosomal dominant 4 (ClinVar).

How common is CAPN3 p.Leu144Phe (c.430C>T) in the general population?

CAPN3 p.Leu144Phe (c.430C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CAPN3 p.Leu144Phe (c.430C>T)?

AlphaMissense predicts ambiguous (score 0.484) — an in-silico prediction, not a clinical call.

CAPN3 p.Leu144Phe

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.430C>T · rs1277687577 · VCV3242028

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.484 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

muscular dystrophy, limb-girdle, autosomal dominant 4

Computational evidence

Protein change
AlphaMissense	0.484	ambiguous
REVEL	0.7	pathogenic-leaning
SaProt	LLR -10.25	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 2.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.21 · regional, not allelic
Overall
CADD	24.7	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 0.0011% South Asian · 1/91,084 alleles

Overall 6.84e-05% 1/1,461,868 alleles · very rare

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.Leu144Phe
Coding: c.430C>T
MANE Select: NM_000070
dbSNP: rs1277687577
Type: single nucleotide variant
Location: chr15:42386217 (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 144: 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

For Calpain-3-related limb-girdle muscular dystrophy D4 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

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CAPN3 c.499-1G>A Pathogenic ★★★ same condition
CAPN3 p.Ala702Val Pathogenic ★★★ same condition
CAPN3 p.Ala798Glu Pathogenic ★★★ ⚠ same condition
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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-leu144phe (accessed [today's date]).

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