Is CTBS p.Tyr330Cys (c.989A>G) pathogenic?

CTBS p.Tyr330Cys (c.989A>G) is classified Uncertain significance in CTBS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-14). AlphaMissense: ambiguous (0.4487); Very rare (popmax 0.00267%, afr).

How common is CTBS p.Tyr330Cys (c.989A>G) in the general population?

CTBS p.Tyr330Cys (c.989A>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CTBS p.Tyr330Cys (c.989A>G)?

AlphaMissense predicts ambiguous (score 0.4487) — an in-silico prediction, not a clinical call.

CTBS p.Tyr330Cys

c.989A>G · VCV4007859

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4487 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4487	ambiguous
REVEL	0.264	benign-leaning
SaProt	LLR -15.26	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 1.5, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 19 kb · p 0.43 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,882 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,613,668 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,441
European (non-Finnish)	8.48e-05%	1,179,842

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: CTBS
Protein: p.Tyr330Cys
Coding: c.989A>G
MANE Select: NM_004388
Type: single nucleotide variant
Location: chr1:84555168 (GRCh38)
Gene constraint: LOEUF 1.084 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.87
Residue 330: the gh18 domain

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

Similar variants

CTBS p.Asn357= Benign ★★ same type
CTBS p.Ala284Thr Uncertain significance ★ ⚠ same type
CTBS p.Ala32Val Uncertain significance ★ ⚠ same type
CTBS p.Arg169Ser Uncertain significance ★ ⚠ same type
CTBS p.Arg189Gly Uncertain significance ★ ⚠ same type
CTBS p.Arg277Gln Uncertain significance ★ ⚠ same type
CTBS p.Arg287Cys Uncertain significance ★ ⚠ same type
CTBS p.Arg349Gln 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/ctbs-p-tyr330cys (accessed [today's date]).

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