Is DRD3 p.Pro135His (c.404C>A) pathogenic?

DRD3 p.Pro135His (c.404C>A) is classified Uncertain significance in DRD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-01). AlphaMissense: likely pathogenic (0.9756); Ultra-rare (popmax 0.0117%, amr); Associated with tremor, hereditary essential, 1.

What condition is associated with DRD3 p.Pro135His (c.404C>A)?

DRD3 p.Pro135His (c.404C>A) is associated with tremor, hereditary essential, 1 (ClinVar).

How common is DRD3 p.Pro135His (c.404C>A) in the general population?

DRD3 p.Pro135His (c.404C>A) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about DRD3 p.Pro135His (c.404C>A)?

AlphaMissense predicts likely pathogenic (score 0.9756) — an in-silico prediction, not a clinical call.

DRD3 p.Pro135His

c.404C>A · rs199862630 · VCV1711864

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9756 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

tremor, hereditary essential, 1

Computational evidence

Protein change
AlphaMissense	0.9756	likely pathogenic
REVEL	0.615	indeterminate
SaProt	LLR -16.74	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 43 kb · p 0.073 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0117% Admixed American · 7/59,980 alleles

Filtering AF 0.00544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000558% 9/1,613,710 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,569
Remaining individualsnot grpmax-eligible	0.0016%	62,470
European (non-Finnish)	8.48e-05%	1,179,775

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.Pro135His
Coding: c.404C>A
MANE Select: NM_000796
dbSNP: rs199862630
Type: single nucleotide variant
Location: chr3:114147537 (GRCh38)
Gene constraint: LOEUF 0.604 · pLI 0.66 (gnomAD)
Structure: AlphaFold pLDDT 75.70 · 9 PDB
Residue 135: 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 p.Pro135= Likely benign ★★ same residue
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

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-pro135his (accessed [today's date]).

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