Is DRD5 p.Ser261Pro (c.781T>C) pathogenic?

DRD5 p.Ser261Pro (c.781T>C) is classified Uncertain significance in DRD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-12). AlphaMissense: ambiguous (0.4906); Very rare (popmax 0.00333%, amr).

How common is DRD5 p.Ser261Pro (c.781T>C) in the general population?

DRD5 p.Ser261Pro (c.781T>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about DRD5 p.Ser261Pro (c.781T>C)?

AlphaMissense predicts ambiguous (score 0.4906) — an in-silico prediction, not a clinical call.

DRD5 p.Ser261Pro

c.781T>C · VCV3842470

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4906 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Computational evidence

Protein change
AlphaMissense	0.4906	ambiguous
REVEL	0.324	indeterminate
SaProt	LLR -12.96	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.35	GERP -3.7, phastCons 0.021
Regional constraint	o/e 1.15	unconstrained · MANE · 1,430 bp · p 9.4e-05 · regional, not allelic
Overall
CADD	20.2	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 0.00333% Admixed American · 2/60,004 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000274% 4/1,461,450 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,002
Remaining individualsnot grpmax-eligible	0.0016%	62,478
European (non-Finnish)	8.48e-05%	1,179,754

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.Ser261Pro
Coding: c.781T>C
MANE Select: NM_000798
Type: single nucleotide variant
Location: chr4:9782810 (GRCh38)
Gene constraint: LOEUF 1.851 · pLI 0.09 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.45 · 1 PDB
Residue 261: an α-helix

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-ser261pro (accessed [today's date]).

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