Is CTLA4 p.Leu25= (c.75G>C) pathogenic?

CTLA4 p.Leu25= (c.75G>C) is classified Benign in CTLA4 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-03). Low-frequency (popmax 2.51%, afr); Associated with autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency.

How common is CTLA4 p.Leu25= (c.75G>C) in the general population?

CTLA4 p.Leu25= (c.75G>C) is low-frequency (popmax 2.51%, afr) (gnomAD).

CTLA4 p.Leu25=

Q: What condition is associated with CTLA4 p.Leu25= (c.75G>C)?

CTLA4 p.Leu25= (c.75G>C) is associated with autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (ClinVar).

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.75G>C · rs16840275 · VCV475280

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.51%, afr)

Conditions

autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -4.2, phastCons 0.63
Overall
CADD	0.735	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.51% African / African-American · 1,880/75,004 alleles

Filtering AF 2.41% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.37%

Overall 0.138% 2,225/1,613,994 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.51%	40
Remaining individualsnot grpmax-eligible	0.234%	428
Middle Eastern	0.231%	433
Admixed American	0.193%	517
South Asian	0.011%	9,108
East Asian	0.00668%	14,964
European (non-Finnish)	0.00475%	21,069

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.Leu25=
Coding: c.75G>C
MANE Select: NM_005214
dbSNP: rs16840275
Type: single nucleotide variant
Location: chr2:203868017 (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-leu25 (accessed [today's date]).

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