Is CTLA4 p.Pro158Ser (c.472C>T) pathogenic?

CTLA4 p.Pro158Ser (c.472C>T) is classified Uncertain significance in CTLA4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-12). AlphaMissense: likely benign (0.2358); Very rare (popmax 0.00169%, nfe); Associated with autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency.

What condition is associated with CTLA4 p.Pro158Ser (c.472C>T)?

CTLA4 p.Pro158Ser (c.472C>T) is associated with autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (ClinVar).

How common is CTLA4 p.Pro158Ser (c.472C>T) in the general population?

CTLA4 p.Pro158Ser (c.472C>T) is very rare (popmax 0.00169%, nfe) (gnomAD).

What do computational predictors say about CTLA4 p.Pro158Ser (c.472C>T)?

AlphaMissense predicts likely benign (score 0.2358) — an in-silico prediction, not a clinical call.

CTLA4 p.Pro158Ser

Q: How is Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency inherited?

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

c.472C>T · rs1688729782 · VCV3032071

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2358 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

Computational evidence

Protein change
AlphaMissense	0.2358	likely benign
REVEL	0.277	benign-leaning
SaProt	LLR -5.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 2,198 bp · p 3.2e-07 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00169% European (non-Finnish) · 20/1,180,016 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.0015% 22/1,461,874 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,256
European (non-Finnish)grpmax	0.00169%	59,001

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CTLA4
Protein: p.Pro158Ser
Coding: c.472C>T
MANE Select: NM_005214
dbSNP: rs1688729782
Type: single nucleotide variant
Location: chr2:203871392 (GRCh38)
Gene constraint: LOEUF 0.211 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.67 · 22 PDB

Full CTLA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

CTLA4 p.Arg51Ter Pathogenic ★★★ same condition
CTLA4 p.Arg75Trp Pathogenic ★★★ ⚠ same condition
CTLA4 p.Asp153Asn Pathogenic ★★★ ⚠ same condition
CTLA4 p.Cys35Ter Pathogenic ★★★ same condition
CTLA4 p.Pro136Ala Likely pathogenic ★★★ same condition
CTLA4 p.Pro136Leu Likely pathogenic ★★★ same condition
CTLA4 p.Pro136Ser Likely pathogenic ★★★ same condition
CTLA4 p.Pro137Arg Likely 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/ctla4-p-pro158ser (accessed [today's date]).

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