Is CTPS2 p.Ala428Val (c.1283C>T) pathogenic?

CTPS2 p.Ala428Val (c.1283C>T) is classified Uncertain significance in CTPS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-22). AlphaMissense: likely benign (0.106); Very rare (popmax 0.00219%, amr).

How common is CTPS2 p.Ala428Val (c.1283C>T) in the general population?

CTPS2 p.Ala428Val (c.1283C>T) is very rare (popmax 0.00219%, amr) (gnomAD).

What do computational predictors say about CTPS2 p.Ala428Val (c.1283C>T)?

AlphaMissense predicts likely benign (score 0.106) — an in-silico prediction, not a clinical call.

CTPS2 p.Ala428Val

c.1283C>T · VCV4008087

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.106 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00219%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.106	likely benign
REVEL	0.149	moderately benign-leaning
SaProt	LLR -5.92	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 9.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 112 kb · p 2.2e-14 · regional, not allelic
Overall
CADD	20.3	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 0.00219% Admixed American · 1/45,685 alleles

Overall 0.000248% 3/1,209,229 alleles · very rare exomes 2/1,097,294 · genomes 1/111,935 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00219%	45,685
African / African-American	0.00175%	57,204
European (non-Finnish)	0.000112%	894,510

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.Ala428Val
Coding: c.1283C>T
MANE Select: NM_175859
Type: single nucleotide variant
Location: chrX:16667527 (GRCh38)
Structure: AlphaFold pLDDT 91.79 · 8 PDB
Residue 428: the glutamine amidotransferase type-1 domain

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.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
CTPS2 p.Asn99His 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-ala428val (accessed [today's date]).

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