Is DRD4 p.Pro280His (c.839C>A) pathogenic?

DRD4 p.Pro280His (c.839C>A) is classified Uncertain significance in DRD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-23). AlphaMissense: likely benign (0.1239); Very rare (popmax 0.00331%, afr).

How common is DRD4 p.Pro280His (c.839C>A) in the general population?

DRD4 p.Pro280His (c.839C>A) is very rare (popmax 0.00331%, afr) (gnomAD).

What do computational predictors say about DRD4 p.Pro280His (c.839C>A)?

AlphaMissense predicts likely benign (score 0.1239) — an in-silico prediction, not a clinical call.

DRD4 p.Pro280His

c.839C>A · VCV4244803

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1239 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00331%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1239	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -11.94	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.55	GERP -2.1
Regional constraint	o/e 1.44	unconstrained · MANE · 3,295 bp · p 6.5e-29 · regional, not allelic
Overall
CADD	8.88	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 0.00331% African / African-American · 2/60,494 alleles

Filtering AF 0.000548% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000205%

Overall 0.000178% 2/1,123,078 alleles · very rare exomes 0/986,512 · genomes 2/136,566 · joint denominator

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: DRD4
Protein: p.Pro280His
Coding: c.839C>A
MANE Select: NM_000797
Type: single nucleotide variant
Location: chr11:640088 (GRCh38)
Gene constraint: LOEUF 1.952 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.06 · 2 PDB
Residue 280: the '4 x 16 aa approximate tandem repeats of [pa]-a-p-g-l-p-[pqr]-[dg]-p-c-g-p-d-c-a-p' region; a UniProt-annotated variant site (in allele d4.2)

Full DRD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DRD4 p.Pro280= Likely benign ★ same residue
DRD4 p.Asn309Asp Uncertain significance ★★ ⚠ same type
DRD4 p.Ser308Pro Uncertain significance ★★ ⚠ same type
DRD4 p.Ala335Gly Benign ★★ same type
DRD4 p.Gly11Arg Benign ★★ same type
DRD4 p.Leu83= Likely benign ★★ same type
DRD4 p.Pro244= Likely benign ★★ same type
DRD4 p.Pro248= 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/drd4-p-pro280his (accessed [today's date]).

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