Is ADORA2B p.Pro249Arg (c.746C>G) pathogenic?

ADORA2B p.Pro249Arg (c.746C>G) is classified Uncertain significance in ADORA2B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-22). AlphaMissense: likely pathogenic (0.9956); Absent from gnomAD v4.1.

How common is ADORA2B p.Pro249Arg (c.746C>G) in the general population?

ADORA2B p.Pro249Arg (c.746C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ADORA2B p.Pro249Arg (c.746C>G)?

AlphaMissense predicts likely pathogenic (score 0.9956) — an in-silico prediction, not a clinical call.

ADORA2B p.Pro249Arg

c.746C>G · VCV3838710

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9956 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9956	likely pathogenic · top 2% in ADORA2B
REVEL	0.886	moderately pathogenic-leaning
SaProt	LLR -16.04	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 30 kb · p 0.37 · regional, not allelic
Overall
CADD	24.2	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: ADORA2B
Protein: p.Pro249Arg
Coding: c.746C>G
MANE Select: NM_000676
Type: single nucleotide variant
Location: chr17:15975089 (GRCh38)
Gene constraint: LOEUF 1.412 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.56 · 5 PDB
Residue 249: an α-helix

Full ADORA2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADORA2B p.Pro249Ser Uncertain significance ★ ⚠ same residue
ADORA2B p.Ala262= Benign ★★ same type
ADORA2B p.Ala35Val Benign ★★ same type
ADORA2B p.Thr37= Benign ★★ same type
ADORA2B p.Ala244Val Uncertain significance ★ ⚠ same type
ADORA2B p.Ala275Gly Uncertain significance ★ ⚠ same type
ADORA2B p.Ala35Gly Uncertain significance ★ ⚠ same type
ADORA2B p.Ala8Glu Uncertain significance ★ ⚠ 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/adora2b-p-pro249arg (accessed [today's date]).

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