Is ADAR p.Phe609Ser (c.1826T>C) pathogenic?

ADAR p.Phe609Ser (c.1826T>C) is classified Uncertain significance in ADAR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-03). AlphaMissense: likely benign (0.1036); Ultra-rare (popmax 0.0156%, eas); Associated with dyschromatosis symmetrica hereditaria.

What condition is associated with ADAR p.Phe609Ser (c.1826T>C)?

ADAR p.Phe609Ser (c.1826T>C) is associated with dyschromatosis symmetrica hereditaria, Aicardi-Goutieres syndrome 6 (ClinVar).

How common is ADAR p.Phe609Ser (c.1826T>C) in the general population?

ADAR p.Phe609Ser (c.1826T>C) is ultra-rare (popmax 0.0156%, eas) (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.Phe609Ser (c.1826T>C)?

AlphaMissense predicts likely benign (score 0.1036) — an in-silico prediction, not a clinical call.

ADAR p.Phe609Ser

c.1826T>C · rs767850785 · VCV2925297

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1036 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

dyschromatosis symmetrica hereditaria

Computational evidence

Protein change
AlphaMissense	0.1036	likely benign
REVEL	0.463	indeterminate
SaProt	LLR -3.37	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.6	GERP 0.73, phastCons 0.89
Regional constraint	o/e 0.74	unconstrained · MANE · 17 kb · p 1.3e-17 · regional, not allelic
Overall
CADD	18.86	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 0.0156% East Asian · 7/44,888 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.00211% 34/1,614,022 alleles · ultra-rare exomes 32/1,461,876 · genomes 2/152,146 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,413
Remaining individualsnot grpmax-eligible	0.0032%	31,243
European (non-Finnish)	0.00203%	49,168
Admixed American	0.00167%	59,986

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.Phe609Ser
Coding: c.1826T>C
MANE Select: NM_001111
dbSNP: rs767850785
Type: single nucleotide variant
Location: chr1:154597936 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.86 · 24 PDB
Residue 609: the 'disordered' region

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 p.Phe609Leu Uncertain significance ★ ⚠ 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
ADAR p.Gln559Ter 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-phe609ser (accessed [today's date]).

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