Is ADAR p.Leu165Pro (c.494T>C) pathogenic?

ADAR p.Leu165Pro (c.494T>C) is classified Uncertain significance in ADAR (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-15). AlphaMissense: likely pathogenic (0.7164); Very rare (popmax 0.000169%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ADAR p.Leu165Pro (c.494T>C)?

ADAR p.Leu165Pro (c.494T>C) is associated with Inborn genetic diseases (ClinVar).

How common is ADAR p.Leu165Pro (c.494T>C) in the general population?

ADAR p.Leu165Pro (c.494T>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about ADAR p.Leu165Pro (c.494T>C)?

AlphaMissense predicts likely pathogenic (score 0.7164) — an in-silico prediction, not a clinical call.

ADAR p.Leu165Pro

c.494T>C · rs1697924081 · VCV2284034

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7164 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7164	likely pathogenic
REVEL	0.576	indeterminate
SaProt	LLR -15.98	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 6,556 bp · p 0.34 · regional, not allelic
Overall
CADD	25.3	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) · 2/1,180,034 alleles

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

Overall 0.000248% 4/1,614,194 alleles · very rare exomes 4/1,461,892 · genomes 0/152,302 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,510
Finnishnot grpmax-eligible	0.00156%	64,030
European (non-Finnish)grpmax	0.000169%	590,016

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu165Pro
Coding: c.494T>C
MANE Select: NM_001111
dbSNP: rs1697924081
Type: single nucleotide variant
Location: chr1:154602148 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.86 · 24 PDB
Residue 165: the z-binding 1 domain; the 'interaction with z-dna' region; an α-helix

Full ADAR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ADAR p.Leu165His Uncertain significance ★ same residue
ADAR p.Ala515Thr Uncertain significance ★★ ⚠ same condition
ADAR p.Ala549Gly Uncertain significance ★★ same condition
ADAR p.Ala787Val Uncertain significance ★★ ⚠ same condition
ADAR p.Arg1150Gln Uncertain significance ★★ ⚠ same condition
ADAR p.Arg360Gln Uncertain significance ★★ ⚠ same condition
ADAR p.Arg474Gln Uncertain significance ★★ ⚠ same condition
ADAR p.Arg790His Uncertain significance ★★ ⚠ 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-leu165pro (accessed [today's date]).

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