Is CTPS1 p.Phe175Leu (c.525T>G) pathogenic?

CTPS1 p.Phe175Leu (c.525T>G) is classified Uncertain significance in CTPS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-25). AlphaMissense: likely pathogenic (0.9651); Very rare (popmax 0.000848%, nfe).

How common is CTPS1 p.Phe175Leu (c.525T>G) in the general population?

CTPS1 p.Phe175Leu (c.525T>G) is very rare (popmax 0.000848%, nfe) (gnomAD).

What do computational predictors say about CTPS1 p.Phe175Leu (c.525T>G)?

AlphaMissense predicts likely pathogenic (score 0.9651) — an in-silico prediction, not a clinical call.

CTPS1 p.Phe175Leu

c.525T>G · VCV4235756

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9651 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000848%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9651	likely pathogenic
REVEL	0.288	benign-leaning
SaProt	LLR -13.14	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.67	GERP -2.7, phastCons 0.025
Regional constraint	o/e 0.32	constrained · MANE · 3,774 bp · p 6e-10 · regional, not allelic
Overall
CADD	21.3	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 0.000848% European (non-Finnish) · 10/1,179,860 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000684% 10/1,461,664 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: CTPS1
Protein: p.Phe175Leu
Coding: c.525T>G
MANE Select: NM_001905
Type: single nucleotide variant
Location: chr1:40988680 (GRCh38)
Gene constraint: LOEUF 0.423 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.46 · 7 PDB
Residue 175: a β-strand

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

Similar variants

CTPS1 p.Phe175= Likely benign ★ same residue
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

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-phe175leu (accessed [today's date]).

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