Is CTLA4 p.Met90Arg (c.269T>G) pathogenic?

CTLA4 p.Met90Arg (c.269T>G) is classified Uncertain significance in CTLA4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-28). AlphaMissense: likely benign (0.0729); Very rare (popmax 0.00769%, sas); Associated with Inborn genetic diseases.

What condition is associated with CTLA4 p.Met90Arg (c.269T>G)?

CTLA4 p.Met90Arg (c.269T>G) is associated with Inborn genetic diseases, autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (ClinVar).

How common is CTLA4 p.Met90Arg (c.269T>G) in the general population?

CTLA4 p.Met90Arg (c.269T>G) is very rare (popmax 0.00769%, sas) (gnomAD).

What do computational predictors say about CTLA4 p.Met90Arg (c.269T>G)?

AlphaMissense predicts likely benign (score 0.0729) — an in-silico prediction, not a clinical call.

CTLA4 p.Met90Arg

c.269T>G · VCV4235612

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0729 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0729	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -0.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.27	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -0.47	GERP -3
Regional constraint	o/e 0.66	unconstrained · MANE · 2,198 bp · p 3.2e-07 · regional, not allelic
Overall
CADD	14.61	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 0.00769% South Asian · 7/91,082 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.000479% 7/1,461,890 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: CTLA4
Protein: p.Met90Arg
Coding: c.269T>G
MANE Select: NM_005214
Type: single nucleotide variant
Location: chr2:203870745 (GRCh38)
Gene constraint: LOEUF 0.211 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.67 · 22 PDB
Residue 90: a disulfide bond; a β-strand; the ig-like v-type domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

Similar variants

CTLA4 p.Met90Val Uncertain significance ★★ ⚠ same residue
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

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-met90arg (accessed [today's date]).

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