Is DRD1 p.Thr446Ala (c.1336A>G) pathogenic?

DRD1 p.Thr446Ala (c.1336A>G) is classified Uncertain significance in DRD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-16). AlphaMissense: likely benign (0.0641); Very rare (popmax 0.00648%, nfe).

How common is DRD1 p.Thr446Ala (c.1336A>G) in the general population?

DRD1 p.Thr446Ala (c.1336A>G) is very rare (popmax 0.00648%, nfe) (gnomAD).

What do computational predictors say about DRD1 p.Thr446Ala (c.1336A>G)?

AlphaMissense predicts likely benign (score 0.0641) — an in-silico prediction, not a clinical call.

DRD1 p.Thr446Ala

c.1336A>G · rs775956849 · VCV2335981

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0641 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00648%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0641	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -5.99	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 2.9	GERP -0.36, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 298 bp · p 0.38 · regional, not allelic
Overall
CADD	18.96	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 0.00648% European (non-Finnish) · 75/1,156,954 alleles

Filtering AF 0.0053% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.00567% 89/1,570,730 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00992%	10,080
Finnishnot grpmax-eligible	0.00971%	10,297
European (non-Finnish)grpmax	0.00648%	15,426
East Asian	0.00225%	44,350
African / African-American	0.00136%	73,726

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: DRD1
Protein: p.Thr446Ala
Coding: c.1336A>G
MANE Select: NM_000794
dbSNP: rs775956849
Type: single nucleotide variant
Location: chr5:175441764 (GRCh38)
Gene constraint: LOEUF 0.252 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.23 · 34 PDB

Full DRD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DRD1 c.-48G>A Likely benign ★★ same type
DRD1 p.Ala147Thr Uncertain significance ★ ⚠ same type
DRD1 p.Ala166Thr Uncertain significance ★ ⚠ same type
DRD1 p.Ala410Ser Uncertain significance ★ ⚠ same type
DRD1 p.Ala67Ser Uncertain significance ★ ⚠ same type
DRD1 p.Arg52Pro Uncertain significance ★ ⚠ same type
DRD1 p.Asn185Lys Uncertain significance ★ ⚠ same type
DRD1 p.Cys253Ser Uncertain significance ★ ⚠ 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/drd1-p-thr446ala (accessed [today's date]).

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