Is CTPS2 p.Met448Leu (c.1342A>C) pathogenic?

CTPS2 p.Met448Leu (c.1342A>C) is classified Uncertain significance in CTPS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-17). AlphaMissense: ambiguous (0.5389); Very rare (popmax 0.00134%, nfe).

How common is CTPS2 p.Met448Leu (c.1342A>C) in the general population?

CTPS2 p.Met448Leu (c.1342A>C) is very rare (popmax 0.00134%, nfe) (gnomAD).

What do computational predictors say about CTPS2 p.Met448Leu (c.1342A>C)?

AlphaMissense predicts ambiguous (score 0.5389) — an in-silico prediction, not a clinical call.

CTPS2 p.Met448Leu

c.1342A>C · VCV3837264

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5389 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5389	ambiguous
REVEL	0.693	pathogenic-leaning
SaProt	LLR -11.33	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 5.1, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 112 kb · p 2.2e-14 · regional, not allelic
Overall
CADD	23.4	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 0.00134% European (non-Finnish) · 12/893,746 alleles

Filtering AF 0.000716% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000565%

Overall 0.000993% 12/1,208,310 alleles · very rare

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.Met448Leu
Coding: c.1342A>C
MANE Select: NM_175859
Type: single nucleotide variant
Location: chrX:16639198 (GRCh38)
Structure: AlphaFold pLDDT 91.79 · 8 PDB
Residue 448: 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.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-met448leu (accessed [today's date]).

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