Is DBH c.339+2T>C pathogenic?

DBH c.339+2T>C is classified Pathogenic in DBH (ClinVar, Multiple submitters, 18 submitters; last evaluated 2025-12-26). Rare (popmax 0.19%, nfe); Associated with DBH-related disorder.

What condition is associated with DBH c.339+2T>C?

DBH c.339+2T>C is associated with DBH-related disorder, orthostatic hypotension 1 (ClinVar).

How common is DBH c.339+2T>C in the general population?

DBH c.339+2T>C is rare (popmax 0.19%, nfe) (gnomAD).

DBH c.339+2T>C

rs74853476 · VCV1750

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 18 submitters

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.19%, nfe)

Conditions

DBH-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function
Splicing
Splice region	donor +2	canonical splice dinucleotide (donor +2) · inside the BP7-excluded zone
SpliceAI	Δ0.59	donor loss · deltas
Pangolin	Δ0.67	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.8	GERP 1.6, phastCons 1
Non-coding constraint	Z 3.31	1 kb window · o/e 0.79 · regional · uncalibrated
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.19% European (non-Finnish) · 2,240/1,179,610 alleles

Filtering AF 0.183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.181%

Overall 0.151% 2,414/1,600,532 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.19%	527
Remaining individualsnot grpmax-eligible	0.144%	693
Admixed American	0.0634%	1,578
African / African-American	0.0493%	2,027
Middle Eastern	0.0165%	6,056
Finnishnot grpmax-eligible	0.0157%	6,385

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
Coding: c.339+2T>C
MANE Select: NM_000787
dbSNP: rs74853476
Type: single nucleotide variant
Location: chr9:133636712 (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

DBH-related disorder

Also linked: orthostatic hypotension 1

Similar variants

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
DBH p.Arg243Gln 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-c-339-plus-2t-c (accessed [today's date]).

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