Is ADORA2B p.Pro193Ser (c.577C>T) pathogenic?

ADORA2B p.Pro193Ser (c.577C>T) is classified Uncertain significance in ADORA2B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-14). AlphaMissense: ambiguous (0.4965); Very rare (popmax 0.00669%, eas).

How common is ADORA2B p.Pro193Ser (c.577C>T) in the general population?

ADORA2B p.Pro193Ser (c.577C>T) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about ADORA2B p.Pro193Ser (c.577C>T)?

AlphaMissense predicts ambiguous (score 0.4965) — an in-silico prediction, not a clinical call.

ADORA2B p.Pro193Ser

c.577C>T · rs775766252 · VCV3090097

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4965 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4965	ambiguous
REVEL	0.112	moderately benign-leaning
SaProt	LLR -5.74	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
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	23.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00669% East Asian · 3/44,864 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.000342% 5/1,461,884 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,955
South Asian	0.0011%	91,070
European (non-Finnish)	8.47e-05%	1,180,025

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: ADORA2B
Protein: p.Pro193Ser
Coding: c.577C>T
MANE Select: NM_000676
dbSNP: rs775766252
Type: single nucleotide variant
Location: chr17:15974920 (GRCh38)
Gene constraint: LOEUF 1.412 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.56 · 5 PDB
Residue 193: an α-helix

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

Similar variants

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
ADORA2B p.Ala8Pro 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-pro193ser (accessed [today's date]).

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