Is DRD5 p.Ser219Phe (c.656C>T) pathogenic?

DRD5 p.Ser219Phe (c.656C>T) is classified Uncertain significance in DRD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: ambiguous (0.5091); Ultra-rare (popmax 0.0516%, amr); Associated with oculocutaneous albinism type 1A.

What condition is associated with DRD5 p.Ser219Phe (c.656C>T)?

DRD5 p.Ser219Phe (c.656C>T) is associated with oculocutaneous albinism type 1A (ClinVar).

How common is DRD5 p.Ser219Phe (c.656C>T) in the general population?

DRD5 p.Ser219Phe (c.656C>T) is ultra-rare (popmax 0.0516%, amr) (gnomAD).

How is Oculocutaneous albinism type 1 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about DRD5 p.Ser219Phe (c.656C>T)?

AlphaMissense predicts ambiguous (score 0.5091) — an in-silico prediction, not a clinical call.

DRD5 p.Ser219Phe

c.656C>T · VCV4278333

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5091 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0516%, amr)

Conditions

oculocutaneous albinism type 1A

Computational evidence

Protein change
AlphaMissense	0.5091	ambiguous
REVEL	0.417	indeterminate
SaProt	LLR -3.06	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 1,430 bp · p 9.4e-05 · regional, not allelic
Overall
CADD	25.1	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 0.0516% Admixed American · 31/60,026 alleles

Filtering AF 0.0374% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0325%

Overall 0.00558% 90/1,614,008 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0516%	1,936
Middle Eastern	0.0495%	2,019
Remaining individualsnot grpmax-eligible	0.0112%	8,928
European (non-Finnish)	0.00407%	24,581
African / African-American	0.00133%	75,050

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.Ser219Phe
Coding: c.656C>T
MANE Select: NM_000798
Type: single nucleotide variant
Location: chr4:9782685 (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

Disease context

oculocutaneous albinism type 1A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Oculocutaneous albinism type 1 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

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-ser219phe (accessed [today's date]).

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