Is CTPS2 p.Phe492Leu (c.1476T>G) pathogenic?

CTPS2 p.Phe492Leu (c.1476T>G) is classified Likely benign in CTPS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-22). AlphaMissense: ambiguous (0.5542); Absent from gnomAD v4.1.

How common is CTPS2 p.Phe492Leu (c.1476T>G) in the general population?

CTPS2 p.Phe492Leu (c.1476T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CTPS2 p.Phe492Leu (c.1476T>G)?

AlphaMissense predicts ambiguous (score 0.5542) — an in-silico prediction, not a clinical call.

CTPS2 p.Phe492Leu

c.1476T>G · rs2518512370 · VCV2528372

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5542 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5542	ambiguous
REVEL	0.239	benign-leaning
SaProt	LLR -2.08	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 1.3, phastCons 0.99
Regional constraint	o/e 0.64	unconstrained · MANE · 112 kb · p 2.2e-14 · regional, not allelic
Overall
CADD	3.321	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

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: CTPS2
Protein: p.Phe492Leu
Coding: c.1476T>G
MANE Select: NM_175859
dbSNP: rs2518512370
Type: single nucleotide variant
Location: chrX:16617220 (GRCh38)
Structure: AlphaFold pLDDT 91.79 · 8 PDB
Residue 492: the glutamine amidotransferase type-1 domain; 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-phe492leu (accessed [today's date]).

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