Is DRD4 p.Ser53Trp (c.158C>G) pathogenic?

DRD4 p.Ser53Trp (c.158C>G) is classified Uncertain significance in DRD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-22). AlphaMissense: ambiguous (0.4803); Very rare (popmax 0.00731%, eas).

How common is DRD4 p.Ser53Trp (c.158C>G) in the general population?

DRD4 p.Ser53Trp (c.158C>G) is very rare (popmax 0.00731%, eas) (gnomAD).

What do computational predictors say about DRD4 p.Ser53Trp (c.158C>G)?

AlphaMissense predicts ambiguous (score 0.4803) — an in-silico prediction, not a clinical call.

DRD4 p.Ser53Trp

c.158C>G · rs776495106 · VCV3085778

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4803 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00731%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4803	ambiguous
REVEL	0.255	benign-leaning
SaProt	LLR -9.55	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.69	GERP -4.6, phastCons 0.17
Regional constraint	o/e 1.44	unconstrained · MANE · 3,295 bp · p 6.5e-29 · regional, not allelic
Overall
CADD	23.4	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 0.00731% East Asian · 3/41,014 alleles

Filtering AF 0.00194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00026% 4/1,536,524 alleles · very rare exomes 4/1,384,294 · genomes 0/152,230 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00731%	13,671
European (non-Finnish)	8.72e-05%	1,147,056

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.Ser53Trp
Coding: c.158C>G
MANE Select: NM_000797
dbSNP: rs776495106
Type: single nucleotide variant
Location: chr11:637462 (GRCh38)
Gene constraint: LOEUF 1.952 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.06 · 2 PDB
Residue 53: 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-ser53trp (accessed [today's date]).

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