Is CASTOR1 p.Arg99Cys (c.295C>T) pathogenic?

CASTOR1 p.Arg99Cys (c.295C>T) is classified Uncertain significance in CASTOR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-20). AlphaMissense: likely benign (0.1625); Ultra-rare (popmax 0.0757%, eas).

How common is CASTOR1 p.Arg99Cys (c.295C>T) in the general population?

CASTOR1 p.Arg99Cys (c.295C>T) is ultra-rare (popmax 0.0757%, eas) (gnomAD).

What do computational predictors say about CASTOR1 p.Arg99Cys (c.295C>T)?

AlphaMissense predicts likely benign (score 0.1625) — an in-silico prediction, not a clinical call.

CASTOR1 p.Arg99Cys

c.295C>T · VCV3995762

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1625 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0757%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1625	likely benign
REVEL	0.213	benign-leaning
SaProt	LLR -9.47	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP -3.2, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 3,874 bp · p 6.6e-05 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0757% East Asian · 34/44,890 alleles

Filtering AF 0.0557% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0488%

Overall 0.0209% 337/1,613,380 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0757%	1,320
Middle Eastern	0.066%	1,516
South Asian	0.0571%	1,752
Remaining individualsnot grpmax-eligible	0.0288%	3,472
European (non-Finnish)	0.0186%	5,388
Admixed American	0.01%	10,004
African / African-American	0.00533%	18,765

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: CASTOR1
Protein: p.Arg99Cys
Coding: c.295C>T
MANE Select: NM_001037666
Type: single nucleotide variant
Location: chr22:30287450 (GRCh38)
Gene constraint: LOEUF 0.906 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.84 · 11 PDB
Residue 99: the act 1 domain; an α-helix

Full CASTOR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CASTOR1 p.Arg99His Uncertain significance ★ ⚠ same residue
CASTOR1 c.505+2T>C Uncertain significance ★ same type
CASTOR1 p.Ala196Thr Uncertain significance ★ ⚠ same type
CASTOR1 p.Ala198Thr Uncertain significance ★ ⚠ same type
CASTOR1 p.Ala87Val Uncertain significance ★ ⚠ same type
CASTOR1 p.Ala92Thr Uncertain significance ★ ⚠ same type
CASTOR1 p.Ala98Thr Uncertain significance ★ ⚠ same type
CASTOR1 p.Arg145Cys 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/castor1-p-arg99cys (accessed [today's date]).

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