Is CTPS1 p.Pro586fs (c.1757del) pathogenic?

CTPS1 p.Pro586fs (c.1757del) is classified Uncertain significance in CTPS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-14). Very rare (popmax 0.00333%, amr); Associated with combined immunodeficiency due to CTPS1 deficiency.

What condition is associated with CTPS1 p.Pro586fs (c.1757del)?

CTPS1 p.Pro586fs (c.1757del) is associated with combined immunodeficiency due to CTPS1 deficiency (ClinVar).

How common is CTPS1 p.Pro586fs (c.1757del) in the general population?

CTPS1 p.Pro586fs (c.1757del) is very rare (popmax 0.00333%, amr) (gnomAD).

CTPS1 p.Pro586fs

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.1757del · rs1643136255 · VCV3015428

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

combined immunodeficiency due to CTPS1 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (18 of 19, 29 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.11	GERP -3.5, phastCons 0.79

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,024 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000274% 4/1,461,342 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,012
European (non-Finnish)	0.00017%	589,783

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.Pro586fs
Coding: c.1757del
MANE Select: NM_001905
dbSNP: rs1643136255
Type: Deletion
Location: chr1:41010225 (GRCh38)
Gene constraint: LOEUF 0.423 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.46 · 7 PDB
Residue 586: the 'disordered' region

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.Pro586= Likely benign ★ same residue
CTPS1 c.1006-19_1006-18del Benign ★★ same condition
CTPS1 c.1190-10del Benign/Likely benign ★★ same condition
CTPS1 c.555_555+997del Uncertain significance ★ same condition
CTPS1 c.1394-6del Benign ★ same condition
CTPS1 c.555+20_555+31del Likely benign ★ same condition
CTPS1 c.721-9del Benign ★ same condition
CTPS1 c.1692-1G>C Pathogenic ★★ 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-pro586fs (accessed [today's date]).

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