Is DBH p.Pro496Ser (c.1486C>T) pathogenic?

DBH p.Pro496Ser (c.1486C>T) is classified Uncertain significance in DBH (ClinVar, Single submitter, 1 submitter; last evaluated 2020-09-30). AlphaMissense: likely pathogenic (0.8485); Ultra-rare (popmax 0.0165%, mid); Associated with sensorineural hearing loss disorder.

What condition is associated with DBH p.Pro496Ser (c.1486C>T)?

DBH p.Pro496Ser (c.1486C>T) is associated with sensorineural hearing loss disorder (ClinVar).

How common is DBH p.Pro496Ser (c.1486C>T) in the general population?

DBH p.Pro496Ser (c.1486C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about DBH p.Pro496Ser (c.1486C>T)?

AlphaMissense predicts likely pathogenic (score 0.8485) — an in-silico prediction, not a clinical call.

DBH p.Pro496Ser

c.1486C>T · rs2131294957 · VCV984400

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8485 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

sensorineural hearing loss disorder

Computational evidence

Protein change
AlphaMissense	0.8485	likely pathogenic
REVEL	0.793	moderately pathogenic-leaning
SaProt	LLR -13.72	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.4	GERP 1.2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 22 kb · p 0.96 · regional, not allelic
Overall
CADD	26.6	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 0.0165% Middle Eastern · 1/6,062 alleles

Overall 0.000205% 3/1,461,590 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
African / African-American	0.00133%	75,046
European (non-Finnish)	8.47e-05%	1,180,018

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.Pro496Ser
Coding: c.1486C>T
MANE Select: NM_000787
dbSNP: rs2131294957
Type: single nucleotide variant
Location: chr9:133656574 (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 496: a disulfide bond; a β-strand

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

Disease context

sensorineural hearing loss disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DBH c.339+2T>C Pathogenic ★★ same type
DBH c.1024+6C>T Uncertain significance ★★ same type
DBH c.486+15C>T Uncertain significance ★★ same type
DBH c.*393C>T Uncertain significance ★★ same type
DBH p.Ala113Ser Uncertain significance ★★ ⚠ same type
DBH p.Ala259Val Uncertain significance ★★ ⚠ same type
DBH p.Ala383Val Uncertain significance ★★ ⚠ same type
DBH p.Ala506Thr Uncertain significance ★★ ⚠ same type

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-pro496ser (accessed [today's date]).

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