Is DRD4 p.Leu76Pro (c.227T>C) pathogenic?

DRD4 p.Leu76Pro (c.227T>C) is classified Uncertain significance in DRD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: likely pathogenic (0.9903); Very rare (popmax 0.00373%, amr).

How common is DRD4 p.Leu76Pro (c.227T>C) in the general population?

DRD4 p.Leu76Pro (c.227T>C) is very rare (popmax 0.00373%, amr) (gnomAD).

What do computational predictors say about DRD4 p.Leu76Pro (c.227T>C)?

AlphaMissense predicts likely pathogenic (score 0.9903) — an in-silico prediction, not a clinical call.

DRD4 p.Leu76Pro

c.227T>C · rs955881268 · VCV2477760

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9903 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00373%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9903	likely pathogenic · top 3% in DRD4
REVEL	0.872	moderately pathogenic-leaning
SaProt	LLR -14.72	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.7	GERP 2.2, phastCons 1
Regional constraint	o/e 1.44	unconstrained · MANE · 3,295 bp · p 6.5e-29 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00373% Admixed American · 2/53,660 alleles

Filtering AF 0.000618% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000231%

Overall 0.000384% 6/1,564,416 alleles · very rare exomes 5/1,412,360 · genomes 1/152,056 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00373%	26,830
European (non-Finnish)	0.000345%	290,006

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.Leu76Pro
Coding: c.227T>C
MANE Select: NM_000797
dbSNP: rs955881268
Type: single nucleotide variant
Location: chr11:637531 (GRCh38)
Gene constraint: LOEUF 1.952 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.06 · 2 PDB
Residue 76: an α-helix

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

Similar variants

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
DRD4 p.Val398= 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-leu76pro (accessed [today's date]).

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