Is CTPS2 p.Pro539Arg (c.1616C>G) pathogenic?

CTPS2 p.Pro539Arg (c.1616C>G) is classified Uncertain significance in CTPS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-16). AlphaMissense: likely pathogenic (0.9632); Absent from gnomAD v4.1.

How common is CTPS2 p.Pro539Arg (c.1616C>G) in the general population?

CTPS2 p.Pro539Arg (c.1616C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CTPS2 p.Pro539Arg (c.1616C>G)?

AlphaMissense predicts likely pathogenic (score 0.9632) — an in-silico prediction, not a clinical call.

CTPS2 p.Pro539Arg

c.1616C>G · rs1930162195 · VCV3078708

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9632 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9632	likely pathogenic
REVEL	0.866	moderately pathogenic-leaning
SaProt	LLR -16.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 5, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 112 kb · p 2.2e-14 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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: CTPS2
Protein: p.Pro539Arg
Coding: c.1616C>G
MANE Select: NM_175859
dbSNP: rs1930162195
Type: single nucleotide variant
Location: chrX:16609616 (GRCh38)
Structure: AlphaFold pLDDT 91.79 · 8 PDB
Residue 539: 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-pro539arg (accessed [today's date]).

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