Is CAPN5 p.Arg53Gln (c.158G>A) pathogenic?

CAPN5 p.Arg53Gln (c.158G>A) is classified Uncertain significance in CAPN5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-16). AlphaMissense: likely pathogenic (0.8119); Very rare (popmax 0.00891%, eas); Associated with Inborn genetic diseases.

What condition is associated with CAPN5 p.Arg53Gln (c.158G>A)?

CAPN5 p.Arg53Gln (c.158G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CAPN5 p.Arg53Gln (c.158G>A) in the general population?

CAPN5 p.Arg53Gln (c.158G>A) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about CAPN5 p.Arg53Gln (c.158G>A)?

AlphaMissense predicts likely pathogenic (score 0.8119) — an in-silico prediction, not a clinical call.

CAPN5 p.Arg53Gln

c.158G>A · rs142613341 · VCV934840

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8119 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8119	likely pathogenic
REVEL	0.541	indeterminate
SaProt	LLR -10.83	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, 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

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

Grpmax group 0.00891% East Asian · 4/44,872 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00205% 33/1,613,138 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,218
Remaining individualsnot grpmax-eligible	0.0048%	20,834
South Asian	0.00439%	22,769
Admixed American	0.00333%	30,016
European (non-Finnish)	0.00161%	62,105
Finnishnot grpmax-eligible	0.00159%	63,016

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.Arg53Gln
Coding: c.158G>A
MANE Select: NM_004055
dbSNP: rs142613341
Type: single nucleotide variant
Location: chr11:77085044 (GRCh38)
Gene constraint: LOEUF 0.928 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.71 · 1 PDB
Residue 53: the calpain catalytic domain

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.Arg53Ter Uncertain significance ★ 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-arg53gln (accessed [today's date]).

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