Is ADAR p.Arg467His (c.1400G>A) pathogenic?

ADAR p.Arg467His (c.1400G>A) is classified Conflicting classifications of pathogenicity in ADAR (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-14). AlphaMissense: likely benign (0.0656); Very rare (popmax 0.00666%, afr); Associated with Aicardi-Goutieres syndrome 6.

What condition is associated with ADAR p.Arg467His (c.1400G>A)?

ADAR p.Arg467His (c.1400G>A) is associated with Aicardi-Goutieres syndrome 6, dyschromatosis symmetrica hereditaria (ClinVar).

How common is ADAR p.Arg467His (c.1400G>A) in the general population?

ADAR p.Arg467His (c.1400G>A) is very rare (popmax 0.00666%, afr) (gnomAD).

How is Aicardi-Goutières syndrome inherited?

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

What do computational predictors say about ADAR p.Arg467His (c.1400G>A)?

AlphaMissense predicts likely benign (score 0.0656) — an in-silico prediction, not a clinical call.

ADAR p.Arg467His

c.1400G>A · rs192121167 · VCV959599

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0656 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Aicardi-Goutieres syndrome 6

Computational evidence

Protein change
AlphaMissense	0.0656	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -6.50	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 -5.3	GERP -3
Regional constraint	o/e 0.74	unconstrained · MANE · 17 kb · p 1.3e-17 · regional, not allelic
Overall
CADD	0.747	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 0.00666% African / African-American · 5/75,036 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00564% 91/1,614,204 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0507%	1,974
Finnishnot grpmax-eligible	0.0312%	3,202
Remaining individualsnot grpmax-eligible	0.0144%	6,945
African / African-Americangrpmax	0.00666%	15,007
South Asian	0.00549%	18,218
East Asian	0.00446%	22,445
European (non-Finnish)	0.00288%	34,707
Admixed American	0.00167%	60,028

Ashkenazi Jewish 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: ADAR
Protein: p.Arg467His
Coding: c.1400G>A
MANE Select: NM_001111
dbSNP: rs192121167
Type: single nucleotide variant
Location: chr1:154601242 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.86 · 24 PDB

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

Disease context

Aicardi-Goutieres syndrome 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dyschromatosis symmetrica hereditaria

For Aicardi-Goutières syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Antenatal, Infancy, Neonatal
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

ADAR p.Arg467Cys Uncertain significance ★ ⚠ same residue
ADAR p.Arg467= Likely benign ★ same residue
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

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-arg467his (accessed [today's date]).

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