Is ADRA1D p.Arg166Cys (c.496C>T) pathogenic?

ADRA1D p.Arg166Cys (c.496C>T) is classified Uncertain significance in ADRA1D (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-01). AlphaMissense: likely pathogenic (0.8563); Absent from gnomAD v4.1.

How common is ADRA1D p.Arg166Cys (c.496C>T) in the general population?

ADRA1D p.Arg166Cys (c.496C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ADRA1D p.Arg166Cys (c.496C>T)?

AlphaMissense predicts likely pathogenic (score 0.8563) — an in-silico prediction, not a clinical call.

ADRA1D p.Arg166Cys

c.496C>T · rs753011248 · VCV2492280

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8563 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8563	likely pathogenic
REVEL	0.742	pathogenic-leaning
SaProt	LLR -13.00	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -0.12, phastCons 0.98
Regional constraint	o/e 1.00	unconstrained · MANE · 27 kb · p 0.98 · regional, not allelic
Overall
CADD	25.1	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

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: ADRA1D
Protein: p.Arg166Cys
Coding: c.496C>T
MANE Select: NM_000678
dbSNP: rs753011248
Type: single nucleotide variant
Location: chr20:4248462 (GRCh38)
Gene constraint: LOEUF 1.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.88

Full ADRA1D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADRA1D p.Arg166Ser Uncertain significance ★ ⚠ same residue
ADRA1D p.Ala174Val Uncertain significance ★ ⚠ same type
ADRA1D p.Ala20Gly Uncertain significance ★ ⚠ same type
ADRA1D p.Ala20Thr Uncertain significance ★ ⚠ same type
ADRA1D p.Ala218Val Uncertain significance ★ ⚠ same type
ADRA1D p.Ala255Pro Uncertain significance ★ ⚠ same type
ADRA1D p.Ala35Gly Uncertain significance ★ ⚠ same type
ADRA1D p.Ala36Gly Uncertain significance ★ ⚠ same type

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/adra1d-p-arg166cys (accessed [today's date]).

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