Is CTLA4 p.Arg75= (c.223C>A) pathogenic?

CTLA4 p.Arg75= (c.223C>A) is classified Likely benign in CTLA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-08). Absent from gnomAD v4.1; Associated with autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency.

What condition is associated with CTLA4 p.Arg75= (c.223C>A)?

CTLA4 p.Arg75= (c.223C>A) is associated with autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (ClinVar).

How common is CTLA4 p.Arg75= (c.223C>A) in the general population?

CTLA4 p.Arg75= (c.223C>A) is absent from gnomAD v4.1 (gnomAD).

CTLA4 p.Arg75=

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.223C>A · rs1688714312 · VCV2022188

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 1.5	GERP 0.53, phastCons 0.99
Overall
CADD	10.05	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CTLA4
Protein: p.Arg75=
Coding: c.223C>A
MANE Select: NM_005214
dbSNP: rs1688714312
Type: single nucleotide variant
Location: chr2:203870699 (GRCh38)
Gene constraint: LOEUF 0.211 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.67 · 22 PDB
Residue 75: 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

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.Arg75Trp Pathogenic ★★★ ⚠ same residue
CTLA4 p.Arg75Gln Uncertain significance ★★ ⚠ same residue
CTLA4 p.Arg51Ter 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-arg75 (accessed [today's date]).

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