Is CAPN11 p.Arg454Trp (c.1360C>T) pathogenic?

CAPN11 p.Arg454Trp (c.1360C>T) is classified Uncertain significance in CAPN11 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-28). AlphaMissense: ambiguous (0.5481); Very rare (popmax 0.00381%, nfe).

How common is CAPN11 p.Arg454Trp (c.1360C>T) in the general population?

CAPN11 p.Arg454Trp (c.1360C>T) is very rare (popmax 0.00381%, nfe) (gnomAD).

What do computational predictors say about CAPN11 p.Arg454Trp (c.1360C>T)?

AlphaMissense predicts ambiguous (score 0.5481) — an in-silico prediction, not a clinical call.

CAPN11 p.Arg454Trp

c.1360C>T · VCV3484740

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5481 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00381%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5481	ambiguous
REVEL	0.593	indeterminate
SaProt	LLR -13.44	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.33	GERP -3.9, phastCons 0.026
Regional constraint	o/e 0.95	unconstrained · MANE · 25 kb · p 0.17 · regional, not allelic
Overall
CADD	23.2	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 0.00381% European (non-Finnish) · 45/1,179,862 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00291% 47/1,613,754 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00381%	26,219
East Asian	0.00223%	44,886
South Asian	0.0011%	91,080

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.Arg454Trp
Coding: c.1360C>T
MANE Select: NM_007058
Type: single nucleotide variant
Location: chr6:44177364 (GRCh38)
Gene constraint: LOEUF 1.194 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.10
Residue 454: 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.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-arg454trp (accessed [today's date]).

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