Is CTPS1 p.Val433Ile (c.1297G>A) pathogenic?

CTPS1 p.Val433Ile (c.1297G>A) is classified Uncertain significance in CTPS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: likely benign (0.0941); Absent from gnomAD v4.1.

How common is CTPS1 p.Val433Ile (c.1297G>A) in the general population?

CTPS1 p.Val433Ile (c.1297G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CTPS1 p.Val433Ile (c.1297G>A)?

AlphaMissense predicts likely benign (score 0.0941) — an in-silico prediction, not a clinical call.

CTPS1 p.Val433Ile

c.1297G>A · VCV4657529

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0941 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0941	likely benign
REVEL	0.144	moderately benign-leaning
SaProt	LLR -7.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.33	acceptor loss at this position · masked 0 · deltas
Pangolin	Δ0.27	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 19 kb · p 1.3e-11 · regional, not allelic
Overall
CADD	24.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CTPS1
Protein: p.Val433Ile
Coding: c.1297G>A
MANE Select: NM_001905
Type: single nucleotide variant
Location: chr1:41007449 (GRCh38)
Gene constraint: LOEUF 0.423 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.46 · 7 PDB
Residue 433: the glutamine amidotransferase type-1 domain; a β-strand

Full CTPS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CTPS1 c.1692-1G>C Pathogenic ★★ same type
CTPS1 c.1095-5T>G Uncertain significance ★★ same type
CTPS1 p.Ala471Thr Uncertain significance ★★ ⚠ same type
CTPS1 p.Arg102Trp Uncertain significance ★★ ⚠ same type
CTPS1 p.Arg294His Uncertain significance ★★ ⚠ same type
CTPS1 p.Arg376Gln Uncertain significance ★★ ⚠ same type
CTPS1 p.Arg550Gln Uncertain significance ★★ ⚠ same type
CTPS1 p.Asn412Ser 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/ctps1-p-val433ile (accessed [today's date]).

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