Is DRD3 p.Val136Ile (c.406G>A) pathogenic?

DRD3 p.Val136Ile (c.406G>A) is classified Conflicting classifications of pathogenicity in DRD3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-06). AlphaMissense: likely benign (0.1023); Rare (popmax 0.456%, sas); Associated with tremor, hereditary essential, 1.

What condition is associated with DRD3 p.Val136Ile (c.406G>A)?

DRD3 p.Val136Ile (c.406G>A) is associated with tremor, hereditary essential, 1 (ClinVar).

How common is DRD3 p.Val136Ile (c.406G>A) in the general population?

DRD3 p.Val136Ile (c.406G>A) is rare (popmax 0.456%, sas) (gnomAD).

What do computational predictors say about DRD3 p.Val136Ile (c.406G>A)?

AlphaMissense predicts likely benign (score 0.1023) — an in-silico prediction, not a clinical call.

DRD3 p.Val136Ile

c.406G>A · rs145218071 · VCV899696

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1023 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.456%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tremor, hereditary essential, 1

Computational evidence

Protein change
AlphaMissense	0.1023	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -4.96	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 5.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 43 kb · p 0.073 · regional, not allelic
Overall
CADD	23.1	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 0.456% South Asian · 415/91,058 alleles

Filtering AF 0.42% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.405%

Overall 0.0312% 503/1,613,724 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.456%	219
Middle Eastern	0.066%	1,516
Remaining individualsnot grpmax-eligible	0.0128%	7,811
African / African-American	0.00667%	15,000
European (non-Finnish)	0.00568%	17,608
Finnishnot grpmax-eligible	0.00312%	32,005
East Asian	0.00223%	44,848
Admixed American	0.00167%	60,004

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: DRD3
Protein: p.Val136Ile
Coding: c.406G>A
MANE Select: NM_000796
dbSNP: rs145218071
Type: single nucleotide variant
Location: chr3:114147535 (GRCh38)
Gene constraint: LOEUF 0.604 · pLI 0.66 (gnomAD)
Structure: AlphaFold pLDDT 75.70 · 9 PDB
Residue 136: a disulfide bond; an α-helix

Full DRD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

tremor, hereditary essential, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DRD3 c.-105G>A Likely benign ★★ same condition
DRD3 c.-333G>A Benign ★★ same condition
DRD3 p.Ala17= Benign ★★ same condition
DRD3 p.Ala38Thr Likely benign ★★ same condition
DRD3 p.Gln240= Benign ★★ same condition
DRD3 p.Gln329= Benign ★★ same condition
DRD3 p.Gly9Ser Benign/Likely benign ★★ same condition
DRD3 p.His359= Benign/Likely benign ★★ same condition

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/drd3-p-val136ile (accessed [today's date]).

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