Is CAPN5 p.Arg438Cys (c.1312C>T) pathogenic?

CAPN5 p.Arg438Cys (c.1312C>T) is classified Uncertain significance in CAPN5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-15). AlphaMissense: likely pathogenic (0.6736); Very rare (popmax 0.0033%, sas).

How common is CAPN5 p.Arg438Cys (c.1312C>T) in the general population?

CAPN5 p.Arg438Cys (c.1312C>T) is very rare (popmax 0.0033%, sas) (gnomAD).

What do computational predictors say about CAPN5 p.Arg438Cys (c.1312C>T)?

AlphaMissense predicts likely pathogenic (score 0.6736) — an in-silico prediction, not a clinical call.

CAPN5 p.Arg438Cys

c.1312C>T · rs372227864 · VCV1471448

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6736 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0033%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6736	likely pathogenic
REVEL	0.796	moderately pathogenic-leaning
SaProt	LLR -12.34	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 6	GERP 1.8, 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 0.0033% South Asian · 3/90,892 alleles

Filtering AF 0.00208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00242% 39/1,611,750 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0033%	30,297
European (non-Finnish)	0.00288%	34,680
Admixed American	0.00167%	59,940
Remaining individualsnot grpmax-eligible	0.0016%	62,424

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.Arg438Cys
Coding: c.1312C>T
MANE Select: NM_004055
dbSNP: rs372227864
Type: single nucleotide variant
Location: chr11:77120734 (GRCh38)
Gene constraint: LOEUF 0.928 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.71 · 1 PDB
Residue 438: the 'domain iii' region

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

Similar variants

CAPN5 p.Arg438Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
HTRA3 p.Arg438Gln Uncertain significance ★ ⚠ same residue
CAPN5 p.Arg438= Likely benign ★ 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

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-arg438cys (accessed [today's date]).

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