Is CTLA4 p.Arg51Ter (c.151C>T) pathogenic?

CTLA4 p.Arg51Ter (c.151C>T) is classified Pathogenic in CTLA4 (ClinVar, Expert panel, 10 submitters; last evaluated 2025-11-24). Absent from gnomAD v4.1; Associated with autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency.

How common is CTLA4 p.Arg51Ter (c.151C>T) in the general population?

CTLA4 p.Arg51Ter (c.151C>T) is absent from gnomAD v4.1 (gnomAD).

CTLA4 p.Arg51Ter

Q: What condition is associated with CTLA4 p.Arg51Ter (c.151C>T)?

CTLA4 p.Arg51Ter (c.151C>T) is associated with autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency, Hashimoto thyroiditis, systemic lupus erythematosus (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.151C>T · rs606231417 · VCV161109

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 10 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

ClinGen expert panel — Antibody Deficiencies VCEP

Pathogenic for autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency. Applied ACMG criteria (verbatim):

PVS1 PM2_Supporting PS4_Moderate

Curation rationale (ClinGen, verbatim)

NM_005214.5(CTLA4):c.151C>T (p.Arg51Ter) is a nonsense variant that introduces a premature stop codon into exon 2 of 4 and is predicted to lead to nonsense-mediated decay in CTLA4, in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 3 apparently unrelated probands meeting the VCEP standard for phenotypic criteria. In 1 case, the proband exceeded 6 phenotypic points with genotyping that excluded causes in other loci (PMID: 25213377, PMID: 29200144). In 2 cases, the proband exceeded 10 phenotype points without genotyping that excluded causes in other loci (PS4_Moderate; PMID: 29729943, PMID:29330115, PMID: 32499327). At least one patient harboring this variant had a phenotype that included hypogammaglobulinemia (2 pts), thrombocytopenia (1 pt), respiratory involvement with pulmonary infiltrates (4 pts), brain infiltrates (1 pts), splenomegaly (2 pts), and eczema (1 pt), but lacked sufficient genotyping to rule out an alternative basis for disease in LRBA, which together were not sufficiently specific to meet PP4 for autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (11 total points, PMID: 29729943). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Antibody Deficiencies VCEP: PVS1, PM2_Supporting, and PS4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/18/2025).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 2 of 4
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 1.5, phastCons 1
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

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.Arg51Ter
Coding: c.151C>T
MANE Select: NM_005214
dbSNP: rs606231417
Type: single nucleotide variant
Location: chr2:203870627 (GRCh38)
Gene constraint: LOEUF 0.211 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.67 · 22 PDB
Residue 51: 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

Also linked: Hashimoto thyroiditis systemic lupus erythematosus type 1 diabetes mellitus 12 celiac disease, susceptibility to, 3

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

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
CTLA4 p.Pro137Leu 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-arg51ter (accessed [today's date]).

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