Is CAPN5 p.Arg435His (c.1304G>A) pathogenic?

CAPN5 p.Arg435His (c.1304G>A) is classified Uncertain significance in CAPN5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-23). AlphaMissense: likely pathogenic (0.7242); Very rare (popmax 0.00447%, eas).

How common is CAPN5 p.Arg435His (c.1304G>A) in the general population?

CAPN5 p.Arg435His (c.1304G>A) is very rare (popmax 0.00447%, eas) (gnomAD).

What do computational predictors say about CAPN5 p.Arg435His (c.1304G>A)?

AlphaMissense predicts likely pathogenic (score 0.7242) — an in-silico prediction, not a clinical call.

CAPN5 p.Arg435His

c.1304G>A · rs781926169 · VCV1425173

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7242 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00447%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7242	likely pathogenic
REVEL	0.863	moderately pathogenic-leaning
SaProt	LLR -13.78	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.45, 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 0.00447% East Asian · 2/44,792 alleles

Filtering AF 0.00074% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000684% 11/1,608,600 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00447%	22,396
Remaining individualsnot grpmax-eligible	0.0016%	62,344
African / African-American	0.00134%	74,862
South Asian	0.0011%	90,652
European (non-Finnish)	0.00051%	196,222

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.Arg435His
Coding: c.1304G>A
MANE Select: NM_004055
dbSNP: rs781926169
Type: single nucleotide variant
Location: chr11:77120726 (GRCh38)
Gene constraint: LOEUF 0.928 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.71 · 1 PDB
Residue 435: the 'domain iii' region

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

Similar variants

CAPN5 p.Arg435Cys Uncertain significance ★ same residue
CAPN5 p.Arg435Leu 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

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-arg435his (accessed [today's date]).

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