Is CTPS1 p.Arg376Pro (c.1127G>C) pathogenic?

CTPS1 p.Arg376Pro (c.1127G>C) is classified Uncertain significance in CTPS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-27). AlphaMissense: likely pathogenic (0.9635); Very rare (popmax 0.000169%, nfe); Associated with combined immunodeficiency due to CTPS1 deficiency.

What condition is associated with CTPS1 p.Arg376Pro (c.1127G>C)?

CTPS1 p.Arg376Pro (c.1127G>C) is associated with combined immunodeficiency due to CTPS1 deficiency (ClinVar).

How common is CTPS1 p.Arg376Pro (c.1127G>C) in the general population?

CTPS1 p.Arg376Pro (c.1127G>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about CTPS1 p.Arg376Pro (c.1127G>C)?

AlphaMissense predicts likely pathogenic (score 0.9635) — an in-silico prediction, not a clinical call.

CTPS1 p.Arg376Pro

Q: How is Severe combined immunodeficiency due to CTPS1 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1127G>C · VCV4781223

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9635 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined immunodeficiency due to CTPS1 deficiency

Computational evidence

Protein change
AlphaMissense	0.9635	likely pathogenic
REVEL	0.947	strongly pathogenic-leaning
SaProt	LLR -13.95	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.31 · evaluated, not missing
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	33.0	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

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,016 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,870 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.Arg376Pro
Coding: c.1127G>C
MANE Select: NM_001905
Type: single nucleotide variant
Location: chr1:41002192 (GRCh38)
Gene constraint: LOEUF 0.423 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.46 · 7 PDB
Residue 376: the glutamine amidotransferase type-1 domain

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

Disease context

combined immunodeficiency due to CTPS1 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Severe combined immunodeficiency due to CTPS1 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

CTPS1 p.Arg376Gln Uncertain significance ★★ ⚠ same residue
CTPS1 p.Arg376= Likely benign ★ same residue
CTPS1 c.1692-1G>C Pathogenic ★★ same condition
CTPS1 c.1095-5T>G Uncertain significance ★★ same condition
CTPS1 p.Ala471Thr Uncertain significance ★★ ⚠ same condition
CTPS1 p.Arg102Trp Uncertain significance ★★ ⚠ same condition
CTPS1 p.Arg294His Uncertain significance ★★ ⚠ same condition
CTPS1 p.Arg550Gln Uncertain significance ★★ ⚠ same condition

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-arg376pro (accessed [today's date]).

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