Is ADAR p.Lys145Arg (c.434A>G) pathogenic?

ADAR p.Lys145Arg (c.434A>G) is classified Uncertain significance in ADAR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-20). AlphaMissense: likely benign (0.0683); Ultra-rare (popmax 0.0117%, amr); Associated with dyschromatosis symmetrica hereditaria.

What condition is associated with ADAR p.Lys145Arg (c.434A>G)?

ADAR p.Lys145Arg (c.434A>G) is associated with dyschromatosis symmetrica hereditaria, Aicardi-Goutieres syndrome 6 (ClinVar).

How common is ADAR p.Lys145Arg (c.434A>G) in the general population?

ADAR p.Lys145Arg (c.434A>G) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

How is Dyschromatosis symmetrica hereditaria inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ADAR p.Lys145Arg (c.434A>G)?

AlphaMissense predicts likely benign (score 0.0683) — an in-silico prediction, not a clinical call.

ADAR p.Lys145Arg

c.434A>G · rs763767761 · VCV1433426

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0683 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dyschromatosis symmetrica hereditaria

Computational evidence

Protein change
AlphaMissense	0.0683	likely benign
REVEL	0.018	moderately benign-leaning
SaProt	LLR -6.63	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 -0.019	GERP -0.75
Regional constraint	o/e 0.96	unconstrained · MANE · 6,556 bp · p 0.34 · regional, not allelic
Overall
CADD	8.266	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 0.0117% Admixed American · 7/60,010 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000743% 12/1,614,118 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,573
Remaining individualsnot grpmax-eligible	0.0016%	62,478
European (non-Finnish)	0.000339%	295,011

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.Lys145Arg
Coding: c.434A>G
MANE Select: NM_001111
dbSNP: rs763767761
Type: single nucleotide variant
Location: chr1:154602208 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.86 · 24 PDB
Residue 145: the z-binding 1 domain; the 'interaction with z-dna' region; an α-helix

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

Disease context

dyschromatosis symmetrica hereditaria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Aicardi-Goutieres syndrome 6

For Dyschromatosis symmetrica hereditaria (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

ADAR c.2885+1G>A Likely pathogenic ★★ same condition
ADAR p.Arg1078Cys Pathogenic ★★ same condition
ADAR p.Arg1096Ter Pathogenic/Likely pathogenic ★★ same condition
ADAR p.Arg328Ter Pathogenic ★★ same condition
ADAR p.Arg360Ter Pathogenic/Likely pathogenic ★★ same condition
ADAR p.Arg474Ter Pathogenic ★★ same condition
ADAR p.Gln559Ter Pathogenic ★★ same condition
ADAR p.Lys1122Gln Likely pathogenic ★★ ⚠ 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-lys145arg (accessed [today's date]).

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