Is CAPN11 p.Ala461Ser (c.1381G>T) pathogenic?

CAPN11 p.Ala461Ser (c.1381G>T) is classified Uncertain significance in CAPN11 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-09). AlphaMissense: likely benign (0.0787); Very rare (popmax 0.00666%, amr).

How common is CAPN11 p.Ala461Ser (c.1381G>T) in the general population?

CAPN11 p.Ala461Ser (c.1381G>T) is very rare (popmax 0.00666%, amr) (gnomAD).

What do computational predictors say about CAPN11 p.Ala461Ser (c.1381G>T)?

AlphaMissense predicts likely benign (score 0.0787) — an in-silico prediction, not a clinical call.

CAPN11 p.Ala461Ser

c.1381G>T · VCV3995156

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0787 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0787	likely benign
REVEL	0.207	benign-leaning
SaProt	LLR -2.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.18	GERP -3.9
Regional constraint	o/e 0.95	unconstrained · MANE · 25 kb · p 0.17 · regional, not allelic
Overall
CADD	0.912	PHRED · no single calibrated threshold — expert panels disagree

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

Grpmax group 0.00666% Admixed American · 4/60,018 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000274% 4/1,461,338 alleles · very rare

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: CAPN11
Protein: p.Ala461Ser
Coding: c.1381G>T
MANE Select: NM_007058
Type: single nucleotide variant
Location: chr6:44177385 (GRCh38)
Gene constraint: LOEUF 1.194 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.10
Residue 461: the 'domain iii' 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.Ala472Thr Uncertain significance ★ ⚠ same type
CAPN11 p.Ala599Thr Uncertain significance ★ ⚠ same type
CAPN11 p.Ala689Glu Uncertain significance ★ ⚠ same type
CAPN11 p.Arg157His 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-ala461ser (accessed [today's date]).

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