Is CTPS1 p.Ala129Val (c.386C>T) pathogenic?

CTPS1 p.Ala129Val (c.386C>T) is classified Uncertain significance in CTPS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-01). AlphaMissense: likely pathogenic (0.8336); Ultra-rare (popmax 0.022%, sas); Associated with combined immunodeficiency due to CTPS1 deficiency.

What condition is associated with CTPS1 p.Ala129Val (c.386C>T)?

CTPS1 p.Ala129Val (c.386C>T) is associated with combined immunodeficiency due to CTPS1 deficiency (ClinVar).

How common is CTPS1 p.Ala129Val (c.386C>T) in the general population?

CTPS1 p.Ala129Val (c.386C>T) is ultra-rare (popmax 0.022%, sas) (gnomAD).

What do computational predictors say about CTPS1 p.Ala129Val (c.386C>T)?

AlphaMissense predicts likely pathogenic (score 0.8336) — an in-silico prediction, not a clinical call.

CTPS1 p.Ala129Val

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.386C>T · rs143058120 · VCV1003774

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8336 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.022%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

combined immunodeficiency due to CTPS1 deficiency

Computational evidence

Protein change
AlphaMissense	0.8336	likely pathogenic
REVEL	0.526	indeterminate
SaProt	LLR -13.09	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 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 2,623 bp · p 0.0011 · regional, not allelic
Overall
CADD	28.3	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 0.022% South Asian · 20/91,070 alleles

Filtering AF 0.0145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00502% 81/1,613,870 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.022%	4,554
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.008%	12,497
European (non-Finnish)	0.00441%	22,691
Admixed American	0.00333%	30,001
African / African-American	0.00134%	74,900

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.Ala129Val
Coding: c.386C>T
MANE Select: NM_001905
dbSNP: rs143058120
Type: single nucleotide variant
Location: chr1:40987420 (GRCh38)
Gene constraint: LOEUF 0.423 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.46 · 7 PDB
Residue 129: 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.Ala129= 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.Arg376Gln 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-ala129val (accessed [today's date]).

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