Is CTLA4 p.Met91Leu (c.271A>T) pathogenic?

CTLA4 p.Met91Leu (c.271A>T) is classified Benign in CTLA4 (ClinVar, Expert panel, 1 submitter; last evaluated 2025-11-24). AlphaMissense: likely benign (0.074); Very rare (popmax 0.00878%, sas); Associated with autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency.

What condition is associated with CTLA4 p.Met91Leu (c.271A>T)?

CTLA4 p.Met91Leu (c.271A>T) is associated with autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (ClinVar).

How common is CTLA4 p.Met91Leu (c.271A>T) in the general population?

CTLA4 p.Met91Leu (c.271A>T) is very rare (popmax 0.00878%, sas) (gnomAD).

What do computational predictors say about CTLA4 p.Met91Leu (c.271A>T)?

AlphaMissense predicts likely benign (score 0.074) — an in-silico prediction, not a clinical call.

CTLA4 p.Met91Leu

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.271A>T · VCV4683127

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.074 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00878%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

Computational evidence

Protein change
AlphaMissense	0.074	likely benign
REVEL	0.005	strongly benign-leaning
SaProt	LLR -1.85	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 0.26	GERP -3
Regional constraint	o/e 0.66	unconstrained · MANE · 2,198 bp · p 3.2e-07 · regional, not allelic
Overall
CADD	3.068	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00878% South Asian · 8/91,088 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.000558% 9/1,614,050 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00878%	11,386
European (non-Finnish)	8.47e-05%	1,180,043

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.Met91Leu
Coding: c.271A>T
MANE Select: NM_005214
Type: single nucleotide variant
Location: chr2:203870747 (GRCh38)
Gene constraint: LOEUF 0.211 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.67 · 22 PDB
Residue 91: a disulfide bond; the ig-like v-type domain

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.Met91Arg Uncertain significance ★ ⚠ same residue
CTLA4 p.Met91fs Pathogenic ★ same residue
CTLA4 p.Met91Ile 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

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-met91leu (accessed [today's date]).

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