Is ADAR p.Val616Phe (c.1846G>T) pathogenic?

ADAR p.Val616Phe (c.1846G>T) is classified Uncertain significance in ADAR (ClinVar, Single submitter, 2 submitters; last evaluated 2021-10-27). AlphaMissense: likely pathogenic (0.732); Very rare (popmax 0.000169%, nfe); Associated with dyschromatosis symmetrica hereditaria.

What condition is associated with ADAR p.Val616Phe (c.1846G>T)?

ADAR p.Val616Phe (c.1846G>T) is associated with dyschromatosis symmetrica hereditaria, Aicardi-Goutieres syndrome 6 (ClinVar).

How common is ADAR p.Val616Phe (c.1846G>T) in the general population?

ADAR p.Val616Phe (c.1846G>T) is very rare (popmax 0.000169%, nfe) (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.Val616Phe (c.1846G>T)?

AlphaMissense predicts likely pathogenic (score 0.732) — an in-silico prediction, not a clinical call.

ADAR p.Val616Phe

c.1846G>T · rs570647049 · VCV1490210

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.732 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

dyschromatosis symmetrica hereditaria

Computational evidence

Protein change
AlphaMissense	0.732	likely pathogenic
REVEL	0.564	indeterminate
SaProt	LLR -12.40	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 17 kb · p 1.3e-17 · regional, not allelic
Overall
CADD	25.6	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) · 2/1,180,000 alleles

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

Overall 0.000137% 2/1,461,872 alleles · very rare

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.Val616Phe
Coding: c.1846G>T
MANE Select: NM_001111
dbSNP: rs570647049
Type: single nucleotide variant
Location: chr1:154597916 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.86 · 24 PDB
Residue 616: the drbm 2 domain

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.Val616Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
ADAR p.Val616= 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-val616phe (accessed [today's date]).

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