Is ADAR p.Pro193Leu (c.578C>T) pathogenic?

ADAR p.Pro193Leu (c.578C>T) is classified Uncertain significance in ADAR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-05). AlphaMissense: ambiguous (0.5013); Absent from gnomAD v4.1; Associated with Aicardi-Goutieres syndrome 6.

What condition is associated with ADAR p.Pro193Leu (c.578C>T)?

ADAR p.Pro193Leu (c.578C>T) is associated with Aicardi-Goutieres syndrome 6 (ClinVar).

How common is ADAR p.Pro193Leu (c.578C>T) in the general population?

ADAR p.Pro193Leu (c.578C>T) is absent from gnomAD v4.1 (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.Pro193Leu (c.578C>T)?

AlphaMissense predicts ambiguous (score 0.5013) — an in-silico prediction, not a clinical call.

ADAR p.Pro193Leu

c.578C>T · rs1697917766 · VCV1032629

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5013 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Aicardi-Goutieres syndrome 6

Computational evidence

Protein change
AlphaMissense	0.5013	ambiguous
REVEL	0.768	pathogenic-leaning
SaProt	LLR -13.04	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 6,556 bp · p 0.34 · regional, not allelic
Overall
CADD	26.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ADAR
Protein: p.Pro193Leu
Coding: c.578C>T
MANE Select: NM_001111
dbSNP: rs1697917766
Type: single nucleotide variant
Location: chr1:154602064 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.86 · 24 PDB
Residue 193: the z-binding 1 domain; a UniProt-annotated variant site (in ags6); the 'interaction with z-dna' region

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

For Aicardi-Goutières syndrome (Orphanet):

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

Similar variants

ADAR p.Pro193Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
ADAR p.Pro193Thr Uncertain significance ★ ⚠ same residue
ADAR p.Pro193fs Pathogenic ★ 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

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-pro193leu (accessed [today's date]).

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