Is ADAR p.Pro756Arg (c.2267C>G) pathogenic?

ADAR p.Pro756Arg (c.2267C>G) is classified Uncertain significance in ADAR (ClinVar, Single submitter, 1 submitter; last evaluated 2026-05-23). AlphaMissense: likely pathogenic (0.9779); Very rare (popmax 0.000169%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ADAR p.Pro756Arg (c.2267C>G)?

ADAR p.Pro756Arg (c.2267C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ADAR p.Pro756Arg (c.2267C>G) in the general population?

ADAR p.Pro756Arg (c.2267C>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about ADAR p.Pro756Arg (c.2267C>G)?

AlphaMissense predicts likely pathogenic (score 0.9779) — an in-silico prediction, not a clinical call.

ADAR p.Pro756Arg

c.2267C>G · VCV4867767

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9779 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9779	likely pathogenic
REVEL	0.773	moderately pathogenic-leaning
SaProt	LLR -11.86	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 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 17 kb · p 1.3e-17 · regional, not allelic
Overall
CADD	29.9	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

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,008 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,612,722 alleles · very rare exomes 1/1,460,670 · genomes 1/152,052 · joint denominator

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: ADAR
Protein: p.Pro756Arg
Coding: c.2267C>G
MANE Select: NM_001111
Type: single nucleotide variant
Location: chr1:154596808 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.86 · 24 PDB
Residue 756: the drbm 3 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ADAR p.Pro756= Likely benign ★ same residue
ADAR p.Ala515Thr Uncertain significance ★★ ⚠ same condition
ADAR p.Ala549Gly Uncertain significance ★★ same condition
ADAR p.Ala787Val Uncertain significance ★★ ⚠ same condition
ADAR p.Arg1150Gln Uncertain significance ★★ ⚠ same condition
ADAR p.Arg360Gln Uncertain significance ★★ ⚠ same condition
ADAR p.Arg474Gln Uncertain significance ★★ ⚠ same condition
ADAR p.Arg790His Uncertain significance ★★ ⚠ same condition

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/adar-p-pro756arg (accessed [today's date]).

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