Is ADARB2 p.Arg254Pro (c.761G>C) pathogenic?

ADARB2 p.Arg254Pro (c.761G>C) is classified Uncertain significance in ADARB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-20). AlphaMissense: likely benign (0.0856); Very rare (popmax 0.00433%, amr).

How common is ADARB2 p.Arg254Pro (c.761G>C) in the general population?

ADARB2 p.Arg254Pro (c.761G>C) is very rare (popmax 0.00433%, amr) (gnomAD).

What do computational predictors say about ADARB2 p.Arg254Pro (c.761G>C)?

AlphaMissense predicts likely benign (score 0.0856) — an in-silico prediction, not a clinical call.

ADARB2 p.Arg254Pro

c.761G>C · rs981640528 · VCV2287568

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0856 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00433%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0856	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -6.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 0.81, phastCons 0.99
Regional constraint	o/e 0.99	unconstrained · MANE · 554 kb · p 0.84 · regional, not allelic
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00433% Admixed American · 1/23,110 alleles

Filtering AF 0.000345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000249%

Overall 0.000958% 12/1,252,204 alleles · very rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.219%	456
Admixed Americangrpmax	0.00433%	23,110
African / African-American	0.00158%	63,238
European (non-Finnish)	0.000801%	124,846

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ADARB2
Protein: p.Arg254Pro
Coding: c.761G>C
MANE Select: NM_018702
dbSNP: rs981640528
Type: single nucleotide variant
Location: chr10:1363344 (GRCh38)
Gene constraint: LOEUF 0.681 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.69

Full ADARB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADARB2 p.Arg457His Uncertain significance ★★ ⚠ same type
ADARB2 p.Arg457Ser Uncertain significance ★★ ⚠ same type
ADARB2 p.Ala125= Likely benign ★★ same type
ADARB2 p.Arg328= Benign ★★ same type
ADARB2 p.Arg657Gln Benign ★★ same type
ADARB2 p.Glu300Lys Benign ★★ ⚠ same type
ADARB2 p.Ser463= Benign ★★ same type
ADARB2 p.Val155= Benign ★★ 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/adarb2-p-arg254pro (accessed [today's date]).

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