Is CTPS2 p.Thr90Met (c.269C>T) pathogenic?

CTPS2 p.Thr90Met (c.269C>T) is classified Uncertain significance in CTPS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-24). AlphaMissense: ambiguous (0.5253); Ultra-rare (popmax 0.0837%, sas).

How common is CTPS2 p.Thr90Met (c.269C>T) in the general population?

CTPS2 p.Thr90Met (c.269C>T) is ultra-rare (popmax 0.0837%, sas) (gnomAD).

What do computational predictors say about CTPS2 p.Thr90Met (c.269C>T)?

AlphaMissense predicts ambiguous (score 0.5253) — an in-silico prediction, not a clinical call.

CTPS2 p.Thr90Met

c.269C>T · VCV3270163

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5253 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0837%, sas)

Computational evidence

Protein change
AlphaMissense	0.5253	ambiguous
REVEL	0.637	indeterminate
SaProt	LLR -13.86	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 2, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 112 kb · p 2.2e-14 · regional, not allelic
Overall
CADD	24.9	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 0.0837% South Asian · 45/53,768 alleles

Filtering AF 0.0642% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0574%

Overall 0.00903% 108/1,196,181 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0837%	1,195
African / African-American	0.0194%	5,164
Remaining individualsnot grpmax-eligible	0.00848%	11,790
European (non-Finnish)	0.00518%	19,297
Admixed American	0.00454%	22,036

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: CTPS2
Protein: p.Thr90Met
Coding: c.269C>T
MANE Select: NM_175859
Type: single nucleotide variant
Location: chrX:16698991 (GRCh38)
Structure: AlphaFold pLDDT 91.79 · 8 PDB
Residue 90: an α-helix

Full CTPS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CTPS2 p.Gly542= Benign ★★ same type
CTPS2 p.Ala315Thr Conflicting classifications of pathogenicity ★ ⚠ same type
CTPS2 p.Ala428Val Uncertain significance ★ ⚠ same type
CTPS2 p.Ala546Thr Uncertain significance ★ ⚠ same type
CTPS2 p.Arg202Cys Uncertain significance ★ ⚠ same type
CTPS2 p.Arg217Gln Uncertain significance ★ ⚠ same type
CTPS2 p.Arg481Gln Uncertain significance ★ ⚠ same type
CTPS2 p.Arg481Trp 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/ctps2-p-thr90met (accessed [today's date]).

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