Is ADRA1B p.Arg357Ser (c.1069C>A) pathogenic?

ADRA1B p.Arg357Ser (c.1069C>A) is classified Uncertain significance in ADRA1B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely pathogenic (0.7483); Ultra-rare (popmax 0.0183%, amr).

How common is ADRA1B p.Arg357Ser (c.1069C>A) in the general population?

ADRA1B p.Arg357Ser (c.1069C>A) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

What do computational predictors say about ADRA1B p.Arg357Ser (c.1069C>A)?

AlphaMissense predicts likely pathogenic (score 0.7483) — an in-silico prediction, not a clinical call.

ADRA1B p.Arg357Ser

c.1069C>A · VCV4245455

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7483 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7483	likely pathogenic
REVEL	0.164	moderately benign-leaning
SaProt	LLR -9.32	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP -1.1, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 55 kb · p 0.01 · regional, not allelic
Overall
CADD	28.9	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 0.0183% Admixed American · 9/49,074 alleles

Filtering AF 0.00949% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00711%

Overall 0.000982% 13/1,323,286 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,453
Ashkenazi Jewishnot grpmax-eligible	0.00773%	12,943
Remaining individualsnot grpmax-eligible	0.0036%	27,746

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: ADRA1B
Protein: p.Arg357Ser
Coding: c.1069C>A
MANE Select: NM_000679
Type: single nucleotide variant
Location: chr5:159971998 (GRCh38)
Gene constraint: LOEUF 1.449 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.95

Full ADRA1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADRA1B p.Ala188Thr Uncertain significance ★ ⚠ same type
ADRA1B p.Ala217Val Uncertain significance ★ ⚠ same type
ADRA1B p.Ala449Thr Uncertain significance ★ ⚠ same type
ADRA1B p.Ala503Thr Uncertain significance ★ ⚠ same type
ADRA1B p.Ala516Glu Uncertain significance ★ ⚠ same type
ADRA1B p.Ala54Pro Uncertain significance ★ ⚠ same type
ADRA1B p.Ala90Asp Uncertain significance ★ ⚠ same type
ADRA1B p.Arg115Gln 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/adra1b-p-arg357ser (accessed [today's date]).

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