Is DBH p.Arg549Cys (c.1645C>T) pathogenic?

DBH p.Arg549Cys (c.1645C>T) is classified Benign in DBH (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.2098); Common (popmax 7.22%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with orthostatic hypotension 1.

What condition is associated with DBH p.Arg549Cys (c.1645C>T)?

DBH p.Arg549Cys (c.1645C>T) is associated with orthostatic hypotension 1 (ClinVar).

How is Dopamine beta-hydroxylase deficiency inherited?

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

What do computational predictors say about DBH p.Arg549Cys (c.1645C>T)?

AlphaMissense predicts likely benign (score 0.2098) — an in-silico prediction, not a clinical call.

DBH p.Arg549Cys

Q: How common is DBH p.Arg549Cys (c.1645C>T) in the general population?

DBH p.Arg549Cys (c.1645C>T) is common (popmax 7.22%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1645C>T · rs6271 · VCV365671

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2098 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 7.22%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

orthostatic hypotension 1

Computational evidence

Protein change
AlphaMissense	0.2098	likely benign
REVEL	0.182	moderately benign-leaning
SaProt	LLR -8.27	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 0.73	GERP -0.99, phastCons 0.18
Regional constraint	o/e 1.00	unconstrained · MANE · 22 kb · p 0.96 · regional, not allelic
Overall
CADD	21.0	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 7.22% European (non-Finnish) · 85,145/1,180,012 alleles

Filtering AF 7.17% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.16%

Overall 6.15% 99,238/1,614,048 alleles · common

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	7.22%	14
Finnishnot grpmax-eligible	6.51%	15
Ashkenazi Jewishnot grpmax-eligible	6.08%	16
Remaining individualsnot grpmax-eligible	5.88%	17
Amishnot grpmax-eligible	4.06%	25
Middle Eastern	4.01%	25
Admixed American	3.99%	25
African / African-American	1.22%	82
South Asian	0.939%	107
East Asian	0.0178%	5,610

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: DBH
Protein: p.Arg549Cys
Coding: c.1645C>T
MANE Select: NM_000787
dbSNP: rs6271
Type: single nucleotide variant
Location: chr9:133657152 (GRCh38)
Gene constraint: LOEUF 0.936 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.58 · 1 PDB
Residue 549: a disulfide bond; a UniProt-annotated variant site (in); an α-helix

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

Disease context

orthostatic hypotension 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Dopamine beta-hydroxylase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy, Neonatal

Similar variants

DBH p.Arg549His Uncertain significance ★★ ⚠ same residue
DBH p.Arg549Leu Uncertain significance ★★ ⚠ same residue
DBH p.Arg549= Likely benign ★ same residue
DBH c.339+2T>C Pathogenic ★★ same condition
DBH c.1024+6C>T Uncertain significance ★★ same condition
DBH c.486+15C>T Uncertain significance ★★ same condition
DBH c.*393C>T Uncertain significance ★★ same condition
DBH p.Ala113Ser Uncertain significance ★★ ⚠ 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/dbh-p-arg549cys (accessed [today's date]).

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