Is DRD4 p.Ile129Ser (c.386T>G) pathogenic?

DRD4 p.Ile129Ser (c.386T>G) is classified Uncertain significance in DRD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-12). AlphaMissense: likely pathogenic (0.9912); Ultra-rare (popmax 0.0495%, mid).

How common is DRD4 p.Ile129Ser (c.386T>G) in the general population?

DRD4 p.Ile129Ser (c.386T>G) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about DRD4 p.Ile129Ser (c.386T>G)?

AlphaMissense predicts likely pathogenic (score 0.9912) — an in-silico prediction, not a clinical call.

DRD4 p.Ile129Ser

c.386T>G · rs751467198 · VCV2390506

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9912 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9912	likely pathogenic · top 3% in DRD4
REVEL	0.866	moderately pathogenic-leaning
SaProt	LLR -14.87	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2, phastCons 1
Regional constraint	o/e 1.44	unconstrained · MANE · 3,295 bp · p 6.5e-29 · regional, not allelic
Overall
CADD	24.7	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 0.0495% Middle Eastern · 3/6,056 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00719%

Overall 0.00332% 53/1,595,950 alleles · ultra-rare exomes 50/1,444,274 · genomes 3/151,676 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,019
European (non-Finnish)	0.00383%	26,135
Remaining individualsnot grpmax-eligible	0.00323%	30,980
South Asian	0.00222%	45,033
African / African-American	0.00134%	74,374

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.Ile129Ser
Coding: c.386T>G
MANE Select: NM_000797
dbSNP: rs751467198
Type: single nucleotide variant
Location: chr11:639533 (GRCh38)
Gene constraint: LOEUF 1.952 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.06 · 2 PDB
Residue 129: 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-ile129ser (accessed [today's date]).

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