Is CAPN5 p.Val84Leu (c.250G>T) pathogenic?

CAPN5 p.Val84Leu (c.250G>T) is classified Conflicting classifications of pathogenicity in CAPN5 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-04). AlphaMissense: likely pathogenic (0.9281); Ultra-rare (popmax 0.0521%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CAPN5 p.Val84Leu (c.250G>T)?

CAPN5 p.Val84Leu (c.250G>T) is associated with Inborn genetic diseases (ClinVar).

How common is CAPN5 p.Val84Leu (c.250G>T) in the general population?

CAPN5 p.Val84Leu (c.250G>T) is ultra-rare (popmax 0.0521%, nfe) (gnomAD).

What do computational predictors say about CAPN5 p.Val84Leu (c.250G>T)?

AlphaMissense predicts likely pathogenic (score 0.9281) — an in-silico prediction, not a clinical call.

CAPN5 p.Val84Leu

c.250G>T · rs201227214 · VCV863947

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9281 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0521%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9281	likely pathogenic
REVEL	0.606	indeterminate
SaProt	LLR -4.20	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.47, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 39 kb · p 0.00098 · regional, not allelic
Overall
CADD	28.7	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 0.0521% European (non-Finnish) · 615/1,179,980 alleles

Filtering AF 0.0486% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0473%

Overall 0.0414% 668/1,612,246 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.072%	1,388
European (non-Finnish)grpmax	0.0521%	1,919
African / African-American	0.0107%	9,384

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val84Leu
Coding: c.250G>T
MANE Select: NM_004055
dbSNP: rs201227214
Type: single nucleotide variant
Location: chr11:77093766 (GRCh38)
Gene constraint: LOEUF 0.928 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.71 · 1 PDB
Residue 84: 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

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-val84leu (accessed [today's date]).

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