Is ADRA1B p.Ser425Leu (c.1274C>T) pathogenic?

ADRA1B p.Ser425Leu (c.1274C>T) is classified Uncertain significance in ADRA1B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-28). AlphaMissense: likely benign (0.1495); Ultra-rare (popmax 0.0324%, eas).

How common is ADRA1B p.Ser425Leu (c.1274C>T) in the general population?

ADRA1B p.Ser425Leu (c.1274C>T) is ultra-rare (popmax 0.0324%, eas) (gnomAD).

What do computational predictors say about ADRA1B p.Ser425Leu (c.1274C>T)?

AlphaMissense predicts likely benign (score 0.1495) — an in-silico prediction, not a clinical call.

ADRA1B p.Ser425Leu

c.1274C>T · rs1466814495 · VCV3090576

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1495 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0324%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1495	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -7.09	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 0.61, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 426 bp · p 0.082 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0324% East Asian · 10/30,890 alleles

Filtering AF 0.0175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0133%

Overall 0.000955% 13/1,361,930 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0324%	3,089
Remaining individualsnot grpmax-eligible	0.00395%	25,300
African / African-American	0.00152%	65,766

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.Ser425Leu
Coding: c.1274C>T
MANE Select: NM_000679
dbSNP: rs1466814495
Type: single nucleotide variant
Location: chr5:159972203 (GRCh38)
Gene constraint: LOEUF 1.449 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.95
Residue 425: the 'disordered' region

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-ser425leu (accessed [today's date]).

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