Is ADRA2C p.Pro280Ser (c.838C>T) pathogenic?

ADRA2C p.Pro280Ser (c.838C>T) is classified Uncertain significance in ADRA2C (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-28). AlphaMissense: likely benign (0.093); Ultra-rare (popmax 0.0237%, nfe).

How common is ADRA2C p.Pro280Ser (c.838C>T) in the general population?

ADRA2C p.Pro280Ser (c.838C>T) is ultra-rare (popmax 0.0237%, nfe) (gnomAD).

What do computational predictors say about ADRA2C p.Pro280Ser (c.838C>T)?

AlphaMissense predicts likely benign (score 0.093) — an in-silico prediction, not a clinical call.

ADRA2C p.Pro280Ser

c.838C>T · rs953574599 · VCV2386721

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.093 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0237%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.093	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	LLR -7.20	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 0.7	GERP -1.5, phastCons 0.59
Regional constraint	o/e 0.87	unconstrained · MANE · 1,385 bp · p 0.00065 · regional, not allelic
Overall
CADD	17.02	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 0.0237% European (non-Finnish) · 269/1,133,926 alleles

Filtering AF 0.0214% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0204%

Overall 0.0188% 282/1,498,540 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0237%	4,215
Remaining individualsnot grpmax-eligible	0.0137%	7,279
African / African-American	0.00719%	13,907

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: ADRA2C
Protein: p.Pro280Ser
Coding: c.838C>T
MANE Select: NM_000683
dbSNP: rs953574599
Type: single nucleotide variant
Location: chr4:3767444 (GRCh38)
Gene constraint: LOEUF 1.116 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 74.70 · 1 PDB
Residue 280: the 'disordered' region

Full ADRA2C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADRA2C p.Ala311= Likely benign ★★ same type
ADRA2C p.Ala115Thr Uncertain significance ★ ⚠ same type
ADRA2C p.Ala16Val Uncertain significance ★ ⚠ same type
ADRA2C p.Ala198Asp Uncertain significance ★ ⚠ same type
ADRA2C p.Ala20Val Uncertain significance ★ ⚠ same type
ADRA2C p.Ala249Gly Uncertain significance ★ ⚠ same type
ADRA2C p.Ala266Val Uncertain significance ★ ⚠ same type
ADRA2C p.Ala268Val 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/adra2c-p-pro280ser (accessed [today's date]).

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