Is DRD3 p.Arg254His (c.761G>A) pathogenic?

DRD3 p.Arg254His (c.761G>A) is classified Uncertain significance in DRD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-21). AlphaMissense: likely benign (0.074); Very rare (popmax 0.00329%, sas).

How common is DRD3 p.Arg254His (c.761G>A) in the general population?

DRD3 p.Arg254His (c.761G>A) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about DRD3 p.Arg254His (c.761G>A)?

AlphaMissense predicts likely benign (score 0.074) — an in-silico prediction, not a clinical call.

DRD3 p.Arg254His

c.761G>A · VCV4014831

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.074 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.074	likely benign
REVEL	0.232	benign-leaning
SaProt	LLR -7.16	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 -0.016	GERP -0.92, phastCons 0.001
Regional constraint	o/e 0.92	unconstrained · MANE · 43 kb · p 0.073 · regional, not allelic
Overall
CADD	22.2	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 0.00329% South Asian · 3/91,080 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000616% 9/1,461,862 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,360
Admixed American	0.00167%	60,028
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)	0.000339%	295,005

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: DRD3
Protein: p.Arg254His
Coding: c.761G>A
MANE Select: NM_000796
Type: single nucleotide variant
Location: chr3:114131363 (GRCh38)
Gene constraint: LOEUF 0.604 · pLI 0.66 (gnomAD)
Structure: AlphaFold pLDDT 75.70 · 9 PDB

Full DRD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DRD3 p.Arg254Cys Uncertain significance ★ ⚠ same residue
DRD3 c.-105G>A Likely benign ★★ same type
DRD3 c.-333G>A Benign ★★ same type
DRD3 p.Ala17= Benign ★★ same type
DRD3 p.Ala38Thr Likely benign ★★ same type
DRD3 p.Gln240= Benign ★★ same type
DRD3 p.Gln329= Benign ★★ same type
DRD3 p.Gly9Ser Benign/Likely benign ★★ 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/drd3-p-arg254his (accessed [today's date]).

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