Is ADRA1D p.Arg166Ser (c.496C>A) pathogenic?

ADRA1D p.Arg166Ser (c.496C>A) is classified Uncertain significance in ADRA1D (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-26). AlphaMissense: likely pathogenic (0.8218); Very rare (popmax 0.00669%, eas).

How common is ADRA1D p.Arg166Ser (c.496C>A) in the general population?

ADRA1D p.Arg166Ser (c.496C>A) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about ADRA1D p.Arg166Ser (c.496C>A)?

AlphaMissense predicts likely pathogenic (score 0.8218) — an in-silico prediction, not a clinical call.

ADRA1D p.Arg166Ser

c.496C>A · VCV3273834

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8218 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8218	likely pathogenic
REVEL	0.59	indeterminate
SaProt	LLR -8.47	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
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	23.6	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 0.00669% East Asian · 3/44,822 alleles

Filtering AF 0.00178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.000205% 3/1,460,494 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: ADRA1D
Protein: p.Arg166Ser
Coding: c.496C>A
MANE Select: NM_000678
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.Arg166Cys 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-arg166ser (accessed [today's date]).

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