Is CTPS1 p.Phe541Ser (c.1622T>C) pathogenic?

CTPS1 p.Phe541Ser (c.1622T>C) is classified Uncertain significance in CTPS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-11). AlphaMissense: likely pathogenic (0.6189); Absent from gnomAD v4.1; Associated with combined immunodeficiency due to CTPS1 deficiency.

What condition is associated with CTPS1 p.Phe541Ser (c.1622T>C)?

CTPS1 p.Phe541Ser (c.1622T>C) is associated with combined immunodeficiency due to CTPS1 deficiency (ClinVar).

How common is CTPS1 p.Phe541Ser (c.1622T>C) in the general population?

CTPS1 p.Phe541Ser (c.1622T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CTPS1 p.Phe541Ser (c.1622T>C)?

AlphaMissense predicts likely pathogenic (score 0.6189) — an in-silico prediction, not a clinical call.

CTPS1 p.Phe541Ser

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.1622T>C · rs2148421320 · VCV1495678

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6189 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

combined immunodeficiency due to CTPS1 deficiency

Computational evidence

Protein change
AlphaMissense	0.6189	likely pathogenic
REVEL	0.582	indeterminate
SaProt	LLR -10.03	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 19 kb · p 1.3e-11 · regional, not allelic
Overall
CADD	25.1	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: CTPS1
Protein: p.Phe541Ser
Coding: c.1622T>C
MANE Select: NM_001905
dbSNP: rs2148421320
Type: single nucleotide variant
Location: chr1:41009520 (GRCh38)
Gene constraint: LOEUF 0.423 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.46 · 7 PDB
Residue 541: the glutamine amidotransferase type-1 domain; an α-helix

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.Phe541= Likely benign ★ same residue
CTPS1 p.Phe541Cys Uncertain significance ★ ⚠ 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.Arg376Gln 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-phe541ser (accessed [today's date]).

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