Is DBH p.Pro458Leu (c.1373C>T) pathogenic?

DBH p.Pro458Leu (c.1373C>T) is classified Uncertain significance in DBH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-27). AlphaMissense: likely benign (0.146); Very rare (popmax 0.00667%, afr); Associated with Inborn genetic diseases.

What condition is associated with DBH p.Pro458Leu (c.1373C>T)?

DBH p.Pro458Leu (c.1373C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DBH p.Pro458Leu (c.1373C>T) in the general population?

DBH p.Pro458Leu (c.1373C>T) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about DBH p.Pro458Leu (c.1373C>T)?

AlphaMissense predicts likely benign (score 0.146) — an in-silico prediction, not a clinical call.

DBH p.Pro458Leu

c.1373C>T · VCV3838321

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.146 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.146	likely benign
REVEL	0.402	indeterminate
SaProt	LLR -12.37	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -2.8
Regional constraint	o/e 1.00	unconstrained · MANE · 22 kb · p 0.96 · regional, not allelic
Overall
CADD	15.03	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 0.00667% African / African-American · 5/74,912 alleles

Filtering AF 0.00283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.00322% 52/1,613,278 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,982
European (non-Finnish)	0.00373%	26,819
Admixed American	0.00167%	60,008
Remaining individualsnot grpmax-eligible	0.0016%	62,478
South Asian	0.0011%	91,082

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.Pro458Leu
Coding: c.1373C>T
MANE Select: NM_000787
Type: single nucleotide variant
Location: chr9:133652283 (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 458: 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

Similar variants

DBH p.Pro458= Uncertain significance ★ same residue
DBH p.Ala113Ser Uncertain significance ★★ ⚠ same condition
DBH p.Ala383Val Uncertain significance ★★ ⚠ same condition
DBH p.Arg43His Uncertain significance ★★ ⚠ same condition
DBH p.Arg473Gln Uncertain significance ★★ ⚠ same condition
DBH p.Arg549Leu Uncertain significance ★★ ⚠ same condition
DBH p.Arg572His Uncertain significance ★★ ⚠ same condition
DBH p.Arg6His 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-pro458leu (accessed [today's date]).

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