Is ADAR p.Asn321Ser (c.962A>G) pathogenic?

ADAR p.Asn321Ser (c.962A>G) is classified Uncertain significance in ADAR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-15). AlphaMissense: likely benign (0.221); Ultra-rare (popmax 0.0165%, mid); Associated with Aicardi-Goutieres syndrome 6.

What condition is associated with ADAR p.Asn321Ser (c.962A>G)?

ADAR p.Asn321Ser (c.962A>G) is associated with Aicardi-Goutieres syndrome 6, dyschromatosis symmetrica hereditaria (ClinVar).

How common is ADAR p.Asn321Ser (c.962A>G) in the general population?

ADAR p.Asn321Ser (c.962A>G) is ultra-rare (popmax 0.0165%, mid) (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.Asn321Ser (c.962A>G)?

AlphaMissense predicts likely benign (score 0.221) — an in-silico prediction, not a clinical call.

ADAR p.Asn321Ser

c.962A>G · rs760376737 · VCV1006282

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.221 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Aicardi-Goutieres syndrome 6

Computational evidence

Protein change
AlphaMissense	0.221	likely benign
REVEL	0.222	benign-leaning
SaProt	LLR -5.63	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 2.4	GERP -0.4, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 6,556 bp · p 0.34 · regional, not allelic
Overall
CADD	23.4	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00648% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.006%

Overall 0.00684% 100/1,461,850 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
European (non-Finnish)	0.0078%	12,826
Remaining individualsnot grpmax-eligible	0.0064%	15,628
South Asian	0.0022%	45,545
Admixed American	0.00167%	60,026

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.Asn321Ser
Coding: c.962A>G
MANE Select: NM_001111
dbSNP: rs760376737
Type: single nucleotide variant
Location: chr1:154601680 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.86 · 24 PDB
Residue 321: the z-binding 2 domain; an α-helix

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 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-asn321ser (accessed [today's date]).

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