Is CASP3 p.Arg164Cys (c.490C>T) pathogenic?

CASP3 p.Arg164Cys (c.490C>T) is classified Uncertain significance in CASP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). AlphaMissense: likely pathogenic (0.9258); Very rare (popmax 0.0017%, amr).

How common is CASP3 p.Arg164Cys (c.490C>T) in the general population?

CASP3 p.Arg164Cys (c.490C>T) is very rare (popmax 0.0017%, amr) (gnomAD).

What do computational predictors say about CASP3 p.Arg164Cys (c.490C>T)?

AlphaMissense predicts likely pathogenic (score 0.9258) — an in-silico prediction, not a clinical call.

CASP3 p.Arg164Cys

c.490C>T · VCV4219381

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9258 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0017%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9258	likely pathogenic
REVEL	0.552	indeterminate
SaProt	LLR -14.39	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 7.4	phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 9,178 bp · p 0.0001 · regional, not allelic
Overall
CADD	30.0	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 0.0017% Admixed American · 1/58,878 alleles

Filtering AF 0.000431% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000314%

Overall 0.000812% 13/1,601,410 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0017%	58,878
Remaining individualsnot grpmax-eligible	0.00162%	61,884
South Asian	0.00113%	88,832
European (non-Finnish)	0.000852%	117,430

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: CASP3
Protein: p.Arg164Cys
Coding: c.490C>T
MANE Select: NM_004346
Type: single nucleotide variant
Location: chr4:184631151 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 86.64 · 135 PDB

Full CASP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CASP3 c.*337T>C Benign ★★ same type
CASP3 p.Ala254Thr Uncertain significance ★ ⚠ same type
CASP3 p.Arg79Ser Uncertain significance ★ ⚠ same type
CASP3 p.Cys148Arg Uncertain significance ★ same type
CASP3 p.Gln225Arg Uncertain significance ★ ⚠ same type
CASP3 p.Glu98Gln Uncertain significance ★ ⚠ same type
CASP3 p.Ile126Thr Uncertain significance ★ ⚠ same type
CASP3 p.Ile48Val 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/casp3-p-arg164cys (accessed [today's date]).

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