Is DRD2 p.Val223Ile (c.667G>A) pathogenic?

DRD2 p.Val223Ile (c.667G>A) is classified Uncertain significance in DRD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-26). AlphaMissense: likely benign (0.1223); Ultra-rare (popmax 0.0183%, amr).

How common is DRD2 p.Val223Ile (c.667G>A) in the general population?

DRD2 p.Val223Ile (c.667G>A) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

What do computational predictors say about DRD2 p.Val223Ile (c.667G>A)?

AlphaMissense predicts likely benign (score 0.1223) — an in-silico prediction, not a clinical call.

DRD2 p.Val223Ile

c.667G>A · rs764968856 · VCV287221

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1223 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1223	likely benign
REVEL	0.247	benign-leaning
SaProt	LLR -6.12	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 7.6	GERP 0.29, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 2,833 bp · p 0.35 · regional, not allelic
Overall
CADD	21.1	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 0.0183% Admixed American · 11/60,004 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.000805% 13/1,614,002 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,455
European (non-Finnish)	0.000169%	590,005

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: DRD2
Protein: p.Val223Ile
Coding: c.667G>A
MANE Select: NM_000795
dbSNP: rs764968856
Type: single nucleotide variant
Location: chr11:113415477 (GRCh38)
Gene constraint: LOEUF 0.372 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.49 · 11 PDB
Residue 223: the 'interaction with ppp1r9b' region; an α-helix

Full DRD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DRD2 p.Arg274Gln Uncertain significance ★★ ⚠ same type
DRD2 p.Gln366Lys Uncertain significance ★★ ⚠ same type
DRD2 p.Glu99Lys Uncertain significance ★★ ⚠ same type
DRD2 p.Gly261Arg Uncertain significance ★★ ⚠ same type
DRD2 p.His316Pro Uncertain significance ★★ ⚠ same type
DRD2 p.Ile431Thr Uncertain significance ★★ ⚠ same type
DRD2 p.Pro300His Uncertain significance ★★ ⚠ same type
DRD2 c.1138+65T>G 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/drd2-p-val223ile (accessed [today's date]).

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