Is ADRA2C p.Pro339Ser (c.1015C>T) pathogenic?

ADRA2C p.Pro339Ser (c.1015C>T) is classified Benign in ADRA2C (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-08-19). AlphaMissense: likely benign (0.0765); Low-frequency (popmax 1.14%, eas); Associated with ADRA2C-related disorder.

What condition is associated with ADRA2C p.Pro339Ser (c.1015C>T)?

ADRA2C p.Pro339Ser (c.1015C>T) is associated with ADRA2C-related disorder (ClinVar).

How common is ADRA2C p.Pro339Ser (c.1015C>T) in the general population?

ADRA2C p.Pro339Ser (c.1015C>T) is low-frequency (popmax 1.14%, eas) (gnomAD).

What do computational predictors say about ADRA2C p.Pro339Ser (c.1015C>T)?

AlphaMissense predicts likely benign (score 0.0765) — an in-silico prediction, not a clinical call.

ADRA2C p.Pro339Ser

c.1015C>T · rs189771994 · VCV3050754

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0765 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.14%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ADRA2C-related disorder

Computational evidence

Protein change
AlphaMissense	0.0765	likely benign
REVEL	0.026	moderately benign-leaning
SaProt	LLR -7.04	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 3.5	GERP -0.65, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 1,385 bp · p 0.00065 · regional, not allelic
Overall
CADD	16.44	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 1.14% East Asian · 367/32,290 alleles

Filtering AF 1.04% ClinGen BA1/BS1 input FAF95, joint · FAF99 1%

Overall 0.0458% 621/1,354,640 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	1.14%	88
Remaining individualsnot grpmax-eligible	0.177%	564
South Asian	0.0708%	1,413
Middle Eastern	0.0506%	1,978
African / African-American	0.0417%	2,398
European (non-Finnish)	0.00856%	11,676
Admixed American	0.00817%	12,244
Ashkenazi Jewishnot grpmax-eligible	0.00514%	19,474
Finnishnot grpmax-eligible	0.00251%	39,856

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.Pro339Ser
Coding: c.1015C>T
MANE Select: NM_000683
dbSNP: rs189771994
Type: single nucleotide variant
Location: chr4:3767621 (GRCh38)
Gene constraint: LOEUF 1.116 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 74.70 · 1 PDB
Residue 339: the 'disordered' region

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

Disease context

ADRA2C-related disorder

Similar variants

ADRA2C p.Ala332= Benign same condition
ADRA2C p.Gly389= Benign same condition
ADRA2C p.Leu99= Likely benign same condition
ADRA2C p.Val104= Likely benign same condition
ADRA2C p.313GGA[1] Likely benign same condition
ADRA2C p.Ala311= Likely benign ★★ same type
ADRA2C p.Ala115Thr Uncertain significance ★ ⚠ same type
ADRA2C p.Ala16Val 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-pro339ser (accessed [today's date]).

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