Is DRD4 p.Val74Met (c.220G>A) pathogenic?

DRD4 p.Val74Met (c.220G>A) is classified Uncertain significance in DRD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-09). AlphaMissense: likely benign (0.2328); Ultra-rare (popmax 0.0167%, mid).

How common is DRD4 p.Val74Met (c.220G>A) in the general population?

DRD4 p.Val74Met (c.220G>A) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about DRD4 p.Val74Met (c.220G>A)?

AlphaMissense predicts likely benign (score 0.2328) — an in-silico prediction, not a clinical call.

DRD4 p.Val74Met

c.220G>A · VCV4870097

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2328 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2328	likely benign
REVEL	0.346	indeterminate
SaProt	LLR -12.36	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.35	GERP -1.6, phastCons 0.27
Regional constraint	o/e 1.44	unconstrained · MANE · 3,295 bp · p 6.5e-29 · regional, not allelic
Overall
CADD	20.8	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 0.0167% Middle Eastern · 1/6,000 alleles

Filtering AF 0.000447% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000167%

Overall 0.000447% 7/1,566,064 alleles · ultra-rare exomes 5/1,413,862 · genomes 2/152,202 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	6,000
African / African-American	0.00269%	37,120
Finnishnot grpmax-eligible	0.00193%	51,810
Remaining individualsnot grpmax-eligible	0.00164%	60,906
European (non-Finnish)	0.000172%	580,461

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.Val74Met
Coding: c.220G>A
MANE Select: NM_000797
Type: single nucleotide variant
Location: chr11:637524 (GRCh38)
Gene constraint: LOEUF 1.952 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.06 · 2 PDB
Residue 74: an α-helix

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

Similar variants

DRD4 p.Val74= Benign ★★ same residue
DRD4 p.Val74Leu Uncertain significance ★ ⚠ same residue
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

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-val74met (accessed [today's date]).

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