Is ADRA1D p.Ser67Arg (c.201C>A) pathogenic?

ADRA1D p.Ser67Arg (c.201C>A) is classified Uncertain significance in ADRA1D (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-27). AlphaMissense: ambiguous (0.4555); Very rare (popmax 0.00455%, amr).

How common is ADRA1D p.Ser67Arg (c.201C>A) in the general population?

ADRA1D p.Ser67Arg (c.201C>A) is very rare (popmax 0.00455%, amr) (gnomAD).

What do computational predictors say about ADRA1D p.Ser67Arg (c.201C>A)?

AlphaMissense predicts ambiguous (score 0.4555) — an in-silico prediction, not a clinical call.

ADRA1D p.Ser67Arg

c.201C>A · rs1039272656 · VCV3090701

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4555 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00455%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4555	ambiguous
REVEL	0.236	benign-leaning
SaProt	LLR -10.37	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP -2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 27 kb · p 0.98 · regional, not allelic
Overall
CADD	24.3	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

Grpmax group 0.00455% Admixed American · 2/43,950 alleles

Filtering AF 0.00129% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0011%

Overall 0.00196% 29/1,482,470 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00455%	21,975
Remaining individualsnot grpmax-eligible	0.0035%	28,566
African / African-American	0.00288%	34,768
European (non-Finnish)	0.00197%	50,773
South Asian	0.00134%	74,394

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.Ser67Arg
Coding: c.201C>A
MANE Select: NM_000678
dbSNP: rs1039272656
Type: single nucleotide variant
Location: chr20:4248757 (GRCh38)
Gene constraint: LOEUF 1.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.88
Residue 67: the 'disordered' region

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

Similar variants

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
ADRA1D p.Ala42Pro 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-ser67arg (accessed [today's date]).

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