Is CAPN5 p.Phe83Leu (c.247T>C) pathogenic?

CAPN5 p.Phe83Leu (c.247T>C) is classified Conflicting classifications of pathogenicity in CAPN5 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-15). AlphaMissense: likely pathogenic (0.9724); Ultra-rare (popmax 0.036%, afr); Associated with Inborn genetic diseases.

What condition is associated with CAPN5 p.Phe83Leu (c.247T>C)?

CAPN5 p.Phe83Leu (c.247T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CAPN5 p.Phe83Leu (c.247T>C) in the general population?

CAPN5 p.Phe83Leu (c.247T>C) is ultra-rare (popmax 0.036%, afr) (gnomAD).

What do computational predictors say about CAPN5 p.Phe83Leu (c.247T>C)?

AlphaMissense predicts likely pathogenic (score 0.9724) — an in-silico prediction, not a clinical call.

CAPN5 p.Phe83Leu

c.247T>C · rs148784108 · VCV1064105

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9724 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.036%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9724	likely pathogenic
REVEL	0.395	indeterminate
SaProt	LLR -8.51	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 0.71, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 39 kb · p 0.00098 · regional, not allelic
Overall
CADD	28.2	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 0.036% African / African-American · 27/74,930 alleles

Filtering AF 0.0254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0219%

Overall 0.00174% 28/1,612,222 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.036%	2,775
Finnishnot grpmax-eligible	0.0016%	62,384

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.Phe83Leu
Coding: c.247T>C
MANE Select: NM_004055
dbSNP: rs148784108
Type: single nucleotide variant
Location: chr11:77093763 (GRCh38)
Gene constraint: LOEUF 0.928 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.71 · 1 PDB
Residue 83: the calpain catalytic domain; an α-helix

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

HTRA3 p.Cys83Tyr Uncertain significance ★ ⚠ same residue
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

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-phe83leu (accessed [today's date]).

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