Is CTLA4 p.Pro154= (c.462A>C) pathogenic?

CTLA4 p.Pro154= (c.462A>C) is classified Likely benign in CTLA4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-09-17). Very rare (popmax 0.000678%, nfe); Associated with CTLA4-related disorder.

What condition is associated with CTLA4 p.Pro154= (c.462A>C)?

CTLA4 p.Pro154= (c.462A>C) is associated with CTLA4-related disorder (ClinVar).

How common is CTLA4 p.Pro154= (c.462A>C) in the general population?

CTLA4 p.Pro154= (c.462A>C) is very rare (popmax 0.000678%, nfe) (gnomAD).

CTLA4 p.Pro154=

c.462A>C · rs2469720726 · VCV3046724

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Conditions

CTLA4-related disorder

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 1.6	GERP 1.6, phastCons 1
Overall
CADD	10.08	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000678% European (non-Finnish) · 8/1,179,722 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000547% 8/1,461,534 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.Pro154=
Coding: c.462A>C
MANE Select: NM_005214
dbSNP: rs2469720726
Type: single nucleotide variant
Location: chr2:203871382 (GRCh38)
Gene constraint: LOEUF 0.211 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.67 · 22 PDB
Residue 154: an α-helix; the 'homodimerization' region

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

Disease context

CTLA4-related disorder

Similar variants

CTLA4 p.Pro154Thr Uncertain significance ★ ⚠ same residue
CTLA4 c.110-2A>G Likely pathogenic ★ same condition
CTLA4 c.457+1G>A Likely pathogenic ★ same condition
CTLA4 p.Tyr139Ter Likely pathogenic ★ same condition
CTLA4 p.Tyr127Cys Conflicting classifications of pathogenicity ★ ⚠ same condition
CTLA4 p.Gln12Ter Pathogenic same condition
CTLA4 p.Phe56fs Likely pathogenic ★ same condition
CTLA4 p.Phe162fs 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-pro154 (accessed [today's date]).

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