Is CAPN5 p.Pro504Leu (c.1511C>T) pathogenic?

CAPN5 p.Pro504Leu (c.1511C>T) is classified Uncertain significance in CAPN5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-06). AlphaMissense: likely benign (0.0888); Very rare (popmax 8.7e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CAPN5 p.Pro504Leu (c.1511C>T)?

CAPN5 p.Pro504Leu (c.1511C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CAPN5 p.Pro504Leu (c.1511C>T) in the general population?

CAPN5 p.Pro504Leu (c.1511C>T) is very rare (popmax 8.7e-05%, nfe) (gnomAD).

What do computational predictors say about CAPN5 p.Pro504Leu (c.1511C>T)?

AlphaMissense predicts likely benign (score 0.0888) — an in-silico prediction, not a clinical call.

CAPN5 p.Pro504Leu

c.1511C>T · VCV3827277

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0888 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.7e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0888	likely benign
REVEL	0.356	indeterminate
SaProt	LLR -9.93	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP -3.7, phastCons 0.055
Regional constraint	o/e 0.89	unconstrained · MANE · 39 kb · p 0.00098 · regional, not allelic
Overall
CADD	21.9	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 8.7e-05% European (non-Finnish) · 1/1,149,588 alleles

Overall 7.12e-05% 1/1,403,990 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: CAPN5
Protein: p.Pro504Leu
Coding: c.1511C>T
MANE Select: NM_004055
Type: single nucleotide variant
Location: chr11:77121957 (GRCh38)
Gene constraint: LOEUF 0.928 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.71 · 1 PDB
Residue 504: the c2 domain

Full CAPN5 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

CAPN5 p.Ala183Ser Uncertain significance ★★ ⚠ same condition
CAPN5 p.Ala237Val Uncertain significance ★★ ⚠ same condition
CAPN5 p.Ala253Thr Uncertain significance ★★ ⚠ same condition
CAPN5 p.Ala34Val Uncertain significance ★★ same condition
CAPN5 p.Ala357Val Uncertain significance ★★ ⚠ same condition
CAPN5 p.Ala362Gly Uncertain significance ★★ ⚠ same condition
CAPN5 p.Ala447Thr Uncertain significance ★★ ⚠ same condition
CAPN5 p.Ala552Ser 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/capn5-p-pro504leu (accessed [today's date]).

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