Is DBH p.Arg43His (c.128G>A) pathogenic?

DBH p.Arg43His (c.128G>A) is classified Uncertain significance in DBH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-10-02). AlphaMissense: likely benign (0.0833); Ultra-rare (popmax 0.011%, sas); Associated with Inborn genetic diseases.

What condition is associated with DBH p.Arg43His (c.128G>A)?

DBH p.Arg43His (c.128G>A) is associated with Inborn genetic diseases, orthostatic hypotension 1 (ClinVar).

How common is DBH p.Arg43His (c.128G>A) in the general population?

DBH p.Arg43His (c.128G>A) is ultra-rare (popmax 0.011%, sas) (gnomAD).

What do computational predictors say about DBH p.Arg43His (c.128G>A)?

AlphaMissense predicts likely benign (score 0.0833) — an in-silico prediction, not a clinical call.

DBH p.Arg43His

c.128G>A · rs779109570 · VCV914992

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0833 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0833	likely benign
REVEL	0.114	moderately benign-leaning
SaProt	LLR -7.82	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 0.85	GERP 0.54
Regional constraint	o/e 1.00	unconstrained · MANE · 22 kb · p 0.96 · regional, not allelic
Overall
CADD	14.42	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 0.011% South Asian · 10/91,082 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.00502% 81/1,613,090 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,108
European (non-Finnish)	0.00551%	18,153
Admixed American	0.00333%	29,997
African / African-American	0.00267%	37,460
East Asian	0.00223%	44,880
Remaining individualsnot grpmax-eligible	0.0016%	62,472

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.Arg43His
Coding: c.128G>A
MANE Select: NM_000787
dbSNP: rs779109570
Type: single nucleotide variant
Location: chr9:133636499 (GRCh38)
Gene constraint: LOEUF 0.936 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.58 · 1 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: orthostatic hypotension 1

Similar variants

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
DBH p.Ala259Val Uncertain significance ★★ ⚠ same condition
DBH p.Ala383Val Uncertain significance ★★ ⚠ same condition
DBH p.Ala506Thr 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-arg43his (accessed [today's date]).

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