Is DRD5 p.Leu2Pro (c.5T>C) pathogenic?

DRD5 p.Leu2Pro (c.5T>C) is classified Uncertain significance in DRD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-07). AlphaMissense: likely benign (0.1063); Very rare (popmax 0.00573%, sas).

How common is DRD5 p.Leu2Pro (c.5T>C) in the general population?

DRD5 p.Leu2Pro (c.5T>C) is very rare (popmax 0.00573%, sas) (gnomAD).

What do computational predictors say about DRD5 p.Leu2Pro (c.5T>C)?

AlphaMissense predicts likely benign (score 0.1063) — an in-silico prediction, not a clinical call.

DRD5 p.Leu2Pro

c.5T>C · VCV4014857

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1063 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00573%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1063	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -6.69	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 4.5	GERP -2.8, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 1,430 bp · p 9.4e-05 · regional, not allelic
Overall
CADD	22.1	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 0.00573% South Asian · 4/69,752 alleles

Filtering AF 0.00194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0011%

Overall 0.000307% 4/1,304,366 alleles · very rare

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: DRD5
Protein: p.Leu2Pro
Coding: c.5T>C
MANE Select: NM_000798
Type: single nucleotide variant
Location: chr4:9782034 (GRCh38)
Gene constraint: LOEUF 1.851 · pLI 0.09 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.45 · 1 PDB

Full DRD5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DRD5 p.Val59Met Uncertain significance ★★ ⚠ same type
DRD5 c.-226G>C Benign ★★ same type
DRD5 c.*178G>T Benign ★★ same type
DRD5 p.Leu88Phe Benign ★★ ⚠ same type
DRD5 c.*47T>C Conflicting classifications of pathogenicity ★ same type
DRD5 p.Ala10Val Uncertain significance ★ ⚠ same type
DRD5 p.Ala111Glu Uncertain significance ★ ⚠ same type
DRD5 p.Ala164Glu 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/drd5-p-leu2pro (accessed [today's date]).

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