Is CTPS2 p.Val253Ile (c.757G>A) pathogenic?

CTPS2 p.Val253Ile (c.757G>A) is classified Uncertain significance in CTPS2 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-06-29). AlphaMissense: likely benign (0.1132); Ultra-rare (popmax 0.0208%, eas); Associated with laterality defects, autosomal dominant.

What condition is associated with CTPS2 p.Val253Ile (c.757G>A)?

CTPS2 p.Val253Ile (c.757G>A) is associated with laterality defects, autosomal dominant (ClinVar).

How common is CTPS2 p.Val253Ile (c.757G>A) in the general population?

CTPS2 p.Val253Ile (c.757G>A) is ultra-rare (popmax 0.0208%, eas) (gnomAD).

What do computational predictors say about CTPS2 p.Val253Ile (c.757G>A)?

AlphaMissense predicts likely benign (score 0.1132) — an in-silico prediction, not a clinical call.

CTPS2 p.Val253Ile

c.757G>A · rs755410764 · VCV2591933

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1132 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0208%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

laterality defects, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.1132	likely benign
REVEL	0.178	moderately benign-leaning
SaProt	LLR -7.00	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.29	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 5.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 112 kb · p 2.2e-14 · regional, not allelic
Overall
CADD	26.2	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 0.0208% East Asian · 7/33,733 alleles

Filtering AF 0.00968% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.00124% 15/1,208,152 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0208%	4,819
Remaining individualsnot grpmax-eligible	0.0126%	7,918
Admixed American	0.0044%	22,748

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.Val253Ile
Coding: c.757G>A
MANE Select: NM_175859
dbSNP: rs755410764
Type: single nucleotide variant
Location: chrX:16689565 (GRCh38)
Structure: AlphaFold pLDDT 91.79 · 8 PDB
Residue 253: an α-helix

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

Disease context

laterality defects, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-val253ile (accessed [today's date]).

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