Is CTLA4 p.Thr72Pro (c.214A>C) pathogenic?

CTLA4 p.Thr72Pro (c.214A>C) is classified Uncertain significance in CTLA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-04-01). AlphaMissense: likely pathogenic (0.9129); Absent from gnomAD v4.1.

How common is CTLA4 p.Thr72Pro (c.214A>C) in the general population?

CTLA4 p.Thr72Pro (c.214A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CTLA4 p.Thr72Pro (c.214A>C)?

AlphaMissense predicts likely pathogenic (score 0.9129) — an in-silico prediction, not a clinical call.

CTLA4 p.Thr72Pro

c.214A>C · rs1206369281 · VCV546886

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9129 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9129	likely pathogenic · top 8% in CTLA4
REVEL	0.488	indeterminate
SaProt	LLR -13.36	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 1.4, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 2,198 bp · p 3.2e-07 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

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.Thr72Pro
Coding: c.214A>C
MANE Select: NM_005214
dbSNP: rs1206369281
Type: single nucleotide variant
Location: chr2:203870690 (GRCh38)
Gene constraint: LOEUF 0.211 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.67 · 22 PDB
Residue 72: 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

Similar variants

CTLA4 p.Thr72Ala Uncertain significance ★ ⚠ same residue
CTLA4 p.Thr72= Likely benign ★ same residue
CTLA4 p.Arg51Ter Pathogenic ★★★ same type
CTLA4 p.Arg75Trp Pathogenic ★★★ ⚠ same type
CTLA4 p.Asp153Asn Pathogenic ★★★ ⚠ same type
CTLA4 p.Cys35Ter Pathogenic ★★★ same type
CTLA4 p.Pro136Ala Likely pathogenic ★★★ same type
CTLA4 p.Pro136Leu Likely pathogenic ★★★ same type

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-thr72pro (accessed [today's date]).

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