Is CAPN3 p.Phe504Leu (c.1512C>G) pathogenic?

CAPN3 p.Phe504Leu (c.1512C>G) is classified Uncertain significance in CAPN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-18). AlphaMissense: likely pathogenic (0.9986); Very rare (popmax 0.00322%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CAPN3 p.Phe504Leu (c.1512C>G)?

CAPN3 p.Phe504Leu (c.1512C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CAPN3 p.Phe504Leu (c.1512C>G) in the general population?

CAPN3 p.Phe504Leu (c.1512C>G) is very rare (popmax 0.00322%, nfe) (gnomAD).

What do computational predictors say about CAPN3 p.Phe504Leu (c.1512C>G)?

AlphaMissense predicts likely pathogenic (score 0.9986) — an in-silico prediction, not a clinical call.

CAPN3 p.Phe504Leu

c.1512C>G · VCV3995244

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9986 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00322%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9986	likely pathogenic · top 1% in CAPN3
REVEL	0.691	pathogenic-leaning
SaProt	LLR -12.61	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 -5.5	GERP -5.3
Regional constraint	o/e 0.96	unconstrained · MANE · 52 kb · p 0.21 · regional, not allelic
Overall
CADD	16.28	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00322% European (non-Finnish) · 38/1,179,652 alleles

Filtering AF 0.00239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.00242% 39/1,613,218 alleles · very rare exomes 38/1,461,042 · genomes 1/152,176 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00322%	31,043
Remaining individualsnot grpmax-eligible	0.0016%	62,448

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.Phe504Leu
Coding: c.1512C>G
MANE Select: NM_000070
Type: single nucleotide variant
Location: chr15:42401798 (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 504: the 'domain iii' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CAPN3 p.Phe504Cys Uncertain significance ★ ⚠ same residue
CAPN3 p.Phe504= Likely benign ★ same residue
CAPN3 p.Ala14Val Uncertain significance ★★ ⚠ same condition
CAPN3 p.Ala335Thr Uncertain significance ★★ ⚠ same condition
CAPN3 p.Ala34Pro Uncertain significance ★★ ⚠ same condition
CAPN3 p.Ala385Val Uncertain significance ★★ ⚠ same condition
CAPN3 p.Ala750Val Uncertain significance ★★ ⚠ same condition
CAPN3 p.Arg386His Uncertain significance ★★ ⚠ 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-phe504leu (accessed [today's date]).

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