Is CAPN5 p.Arg263His (c.788G>A) pathogenic?

CAPN5 p.Arg263His (c.788G>A) is classified Conflicting classifications of pathogenicity in CAPN5 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-28). AlphaMissense: likely benign (0.1513); Ultra-rare (popmax 0.0126%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CAPN5 p.Arg263His (c.788G>A)?

CAPN5 p.Arg263His (c.788G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CAPN5 p.Arg263His (c.788G>A) in the general population?

CAPN5 p.Arg263His (c.788G>A) is ultra-rare (popmax 0.0126%, nfe) (gnomAD).

What do computational predictors say about CAPN5 p.Arg263His (c.788G>A)?

AlphaMissense predicts likely benign (score 0.1513) — an in-silico prediction, not a clinical call.

CAPN5 p.Arg263His

c.788G>A · rs200359404 · VCV965588

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1513 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0126%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1513	likely benign
REVEL	0.698	pathogenic-leaning
SaProt	LLR -7.56	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	Δ0.41	donor loss, 5 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 39 kb · p 0.00098 · regional, not allelic
Overall
CADD	33.0	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 0.0126% European (non-Finnish) · 149/1,179,966 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0103%

Overall 0.0101% 163/1,613,172 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0126%	7,919
Remaining individualsnot grpmax-eligible	0.0112%	8,919
Admixed American	0.00667%	15,002
East Asian	0.00223%	44,904
African / African-American	0.00133%	74,940
South Asian	0.0011%	91,042

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.Arg263His
Coding: c.788G>A
MANE Select: NM_004055
dbSNP: rs200359404
Type: single nucleotide variant
Location: chr11:77115483 (GRCh38)
Gene constraint: LOEUF 0.928 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.71 · 1 PDB
Residue 263: the calpain catalytic domain; a β-strand

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.Arg263Cys Conflicting classifications of pathogenicity ★ ⚠ 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-arg263his (accessed [today's date]).

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