Is ADAR p.Ala515Ser (c.1543G>T) pathogenic?

ADAR p.Ala515Ser (c.1543G>T) is classified Conflicting classifications of pathogenicity in ADAR (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.0797); Ultra-rare (popmax 0.0342%, nfe); Associated with Aicardi-Goutieres syndrome 6.

What condition is associated with ADAR p.Ala515Ser (c.1543G>T)?

ADAR p.Ala515Ser (c.1543G>T) is associated with Aicardi-Goutieres syndrome 6, intellectual disability, dyschromatosis symmetrica hereditaria (ClinVar).

How common is ADAR p.Ala515Ser (c.1543G>T) in the general population?

ADAR p.Ala515Ser (c.1543G>T) is ultra-rare (popmax 0.0342%, nfe) (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.Ala515Ser (c.1543G>T)?

AlphaMissense predicts likely benign (score 0.0797) — an in-silico prediction, not a clinical call.

ADAR p.Ala515Ser

c.1543G>T · rs200830156 · VCV540263

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0797 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0342%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Aicardi-Goutieres syndrome 6

Computational evidence

Protein change
AlphaMissense	0.0797	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -4.99	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 -0.18	GERP -1.9, phastCons 0.48
Regional constraint	o/e 0.74	unconstrained · MANE · 17 kb · p 1.3e-17 · regional, not allelic
Overall
CADD	13.32	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 0.0342% European (non-Finnish) · 404/1,180,040 alleles

Filtering AF 0.0315% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0304%

Overall 0.0254% 410/1,614,046 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0342%	2,921
Remaining individualsnot grpmax-eligible	0.0048%	20,829
African / African-American	0.00267%	37,451
Admixed American	0.00167%	60,002

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.Ala515Ser
Coding: c.1543G>T
MANE Select: NM_001111
dbSNP: rs200830156
Type: single nucleotide variant
Location: chr1:154601099 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.86 · 24 PDB
Residue 515: the drbm 1 domain

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: intellectual disability 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.Ala515Thr 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-ala515ser (accessed [today's date]).

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