Is DRD4 p.Pro378Ser (c.1132C>T) pathogenic?

DRD4 p.Pro378Ser (c.1132C>T) is classified Uncertain significance in DRD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-21). AlphaMissense: likely benign (0.0573); Very rare (popmax 0.0011%, sas).

How common is DRD4 p.Pro378Ser (c.1132C>T) in the general population?

DRD4 p.Pro378Ser (c.1132C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about DRD4 p.Pro378Ser (c.1132C>T)?

AlphaMissense predicts likely benign (score 0.0573) — an in-silico prediction, not a clinical call.

DRD4 p.Pro378Ser

c.1132C>T · rs770833402 · VCV3085776

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0573 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0573	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -11.66	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 -0.066	GERP -3.1, phastCons 0.71
Regional constraint	o/e 1.44	unconstrained · MANE · 3,295 bp · p 6.5e-29 · regional, not allelic
Overall
CADD	10.71	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 0.0011% South Asian · 1/91,082 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00025% 4/1,602,278 alleles · very rare exomes 4/1,449,930 · genomes 0/152,348 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,082
European (non-Finnish)	0.000254%	393,273

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.Pro378Ser
Coding: c.1132C>T
MANE Select: NM_000797
dbSNP: rs770833402
Type: single nucleotide variant
Location: chr11:640475 (GRCh38)
Gene constraint: LOEUF 1.952 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.06 · 2 PDB
Residue 378: 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-pro378ser (accessed [today's date]).

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