Is ADARB2 p.Arg259Cys (c.775C>T) pathogenic?

ADARB2 p.Arg259Cys (c.775C>T) is classified Uncertain significance in ADARB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-26). AlphaMissense: likely benign (0.1344); Very rare (popmax 0.00436%, amr).

How common is ADARB2 p.Arg259Cys (c.775C>T) in the general population?

ADARB2 p.Arg259Cys (c.775C>T) is very rare (popmax 0.00436%, amr) (gnomAD).

What do computational predictors say about ADARB2 p.Arg259Cys (c.775C>T)?

AlphaMissense predicts likely benign (score 0.1344) — an in-silico prediction, not a clinical call.

ADARB2 p.Arg259Cys

c.775C>T · rs1180210627 · VCV2273908

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1344 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00436%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1344	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -8.22	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 5.6	GERP 0.79, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 554 kb · p 0.84 · regional, not allelic
Overall
CADD	23.5	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 0.00436% Admixed American · 1/22,936 alleles

Filtering AF 0.000218% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000143%

Overall 0.000726% 9/1,239,234 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00436%	22,936
East Asian	0.00335%	29,824
African / African-American	0.00159%	63,036
European (non-Finnish)	0.000605%	165,280

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.Arg259Cys
Coding: c.775C>T
MANE Select: NM_018702
dbSNP: rs1180210627
Type: single nucleotide variant
Location: chr10:1363330 (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.Arg259His Likely benign ★ ⚠ same residue
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

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-arg259cys (accessed [today's date]).

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