Is DRD4 p.Pro312Ser (c.934C>T) pathogenic?

DRD4 p.Pro312Ser (c.934C>T) is classified Uncertain significance in DRD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-24). AlphaMissense: likely benign (0.0774); Ultra-rare (popmax 0.011%, afr).

How common is DRD4 p.Pro312Ser (c.934C>T) in the general population?

DRD4 p.Pro312Ser (c.934C>T) is ultra-rare (popmax 0.011%, afr) (gnomAD).

What do computational predictors say about DRD4 p.Pro312Ser (c.934C>T)?

AlphaMissense predicts likely benign (score 0.0774) — an in-silico prediction, not a clinical call.

DRD4 p.Pro312Ser

c.934C>T · rs780003868 · VCV2217049

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0774 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0774	likely benign
REVEL	0.018	moderately benign-leaning
SaProt	LLR -9.04	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 -0.15	GERP -2
Regional constraint	o/e 1.44	unconstrained · MANE · 3,295 bp · p 6.5e-29 · regional, not allelic
Overall
CADD	7.462	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 0.011% African / African-American · 8/72,796 alleles

Filtering AF 0.00541% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0039%

Overall 0.0015% 23/1,529,788 alleles · ultra-rare exomes 14/1,377,614 · genomes 9/152,174 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.011%	9,100
South Asian	0.00956%	10,465
Remaining individualsnot grpmax-eligible	0.00336%	29,802
East Asian	0.00246%	40,696
European (non-Finnish)	0.00035%	286,109

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.Pro312Ser
Coding: c.934C>T
MANE Select: NM_000797
dbSNP: rs780003868
Type: single nucleotide variant
Location: chr11:640183 (GRCh38)
Gene constraint: LOEUF 1.952 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.06 · 2 PDB
Residue 312: 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

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-pro312ser (accessed [today's date]).

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