Is CAPN11 p.Asp653His (c.1957G>C) pathogenic?

CAPN11 p.Asp653His (c.1957G>C) is classified Uncertain significance in CAPN11 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-15). AlphaMissense: likely pathogenic (0.8116); Absent from gnomAD v4.1.

How common is CAPN11 p.Asp653His (c.1957G>C) in the general population?

CAPN11 p.Asp653His (c.1957G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CAPN11 p.Asp653His (c.1957G>C)?

AlphaMissense predicts likely pathogenic (score 0.8116) — an in-silico prediction, not a clinical call.

CAPN11 p.Asp653His

c.1957G>C · VCV4648057

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8116 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8116	likely pathogenic
REVEL	0.882	moderately pathogenic-leaning
SaProt	LLR -14.65	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 25 kb · p 0.17 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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: CAPN11
Protein: p.Asp653His
Coding: c.1957G>C
MANE Select: NM_007058
Type: single nucleotide variant
Location: chr6:44182959 (GRCh38)
Gene constraint: LOEUF 1.194 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.10
Residue 653: a binding site; the ef-hand 2 domain; the 'domain iv' region

Full CAPN11 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAPN11 p.Gln133Ter Likely benign ★★ same type
CAPN11 p.Ala29Pro Uncertain significance ★ ⚠ same type
CAPN11 p.Ala405Pro Uncertain significance ★ ⚠ same type
CAPN11 p.Ala405Thr Uncertain significance ★ ⚠ same type
CAPN11 p.Ala461Ser Uncertain significance ★ ⚠ same type
CAPN11 p.Ala472Thr Uncertain significance ★ ⚠ same type
CAPN11 p.Ala599Thr Uncertain significance ★ ⚠ same type
CAPN11 p.Ala689Glu 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/capn11-p-asp653his (accessed [today's date]).

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