Is DBH p.Pro378Leu (c.1133C>T) pathogenic?

DBH p.Pro378Leu (c.1133C>T) is classified Uncertain significance in DBH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-10-03). AlphaMissense: likely pathogenic (0.5667); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with DBH p.Pro378Leu (c.1133C>T)?

DBH p.Pro378Leu (c.1133C>T) is associated with Inborn genetic diseases, orthostatic hypotension 1 (ClinVar).

How common is DBH p.Pro378Leu (c.1133C>T) in the general population?

DBH p.Pro378Leu (c.1133C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about DBH p.Pro378Leu (c.1133C>T)?

AlphaMissense predicts likely pathogenic (score 0.5667) — an in-silico prediction, not a clinical call.

DBH p.Pro378Leu

c.1133C>T · rs1372358474 · VCV1045487

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5667 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5667	likely pathogenic
REVEL	0.884	moderately pathogenic-leaning
SaProt	LLR -13.06	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 22 kb · p 0.96 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00333% Admixed American · 2/60,012 alleles

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

Overall 0.00041% 6/1,461,712 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,006
European (non-Finnish)	0.000339%	295,008

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.Pro378Leu
Coding: c.1133C>T
MANE Select: NM_000787
dbSNP: rs1372358474
Type: single nucleotide variant
Location: chr9:133647954 (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 378: a disulfide bond

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-pro378leu (accessed [today's date]).

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