Is CAPN5 p.Asp258Glu (c.774T>A) pathogenic?

CAPN5 p.Asp258Glu (c.774T>A) is classified Uncertain significance in CAPN5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-25). AlphaMissense: ambiguous (0.4601); Absent from gnomAD v4.1.

How common is CAPN5 p.Asp258Glu (c.774T>A) in the general population?

CAPN5 p.Asp258Glu (c.774T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CAPN5 p.Asp258Glu (c.774T>A)?

AlphaMissense predicts ambiguous (score 0.4601) — an in-silico prediction, not a clinical call.

CAPN5 p.Asp258Glu

c.774T>A · rs1950457337 · VCV957699

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4601 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4601	ambiguous
REVEL	0.252	benign-leaning
SaProt	LLR -6.71	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.48 · evaluated, not missing
Constraint at this position
Conservation	phyloP -5	GERP -3.8
Regional constraint	o/e 0.89	unconstrained · MANE · 39 kb · p 0.00098 · regional, not allelic
Overall
CADD	11.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CAPN5
Protein: p.Asp258Glu
Coding: c.774T>A
MANE Select: NM_004055
dbSNP: rs1950457337
Type: single nucleotide variant
Location: chr11:77115469 (GRCh38)
Gene constraint: LOEUF 0.928 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.71 · 1 PDB
Residue 258: the calpain catalytic domain; a β-strand

Full CAPN5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN5 p.Asp258Gly Uncertain significance ⚠ same residue
CAPN5 p.Arg243Leu Pathogenic ★★ ⚠ same type
CAPN5 p.Arg289Trp Pathogenic ★★ ⚠ same type
CAPN5 p.Ala118Val Uncertain significance ★★ ⚠ same type
CAPN5 p.Ala183Ser Uncertain significance ★★ ⚠ same type
CAPN5 p.Ala185Val Uncertain significance ★★ ⚠ same type
CAPN5 p.Ala237Val Uncertain significance ★★ ⚠ same type
CAPN5 p.Ala245Val Uncertain significance ★★ ⚠ same type

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-asp258glu (accessed [today's date]).

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