Is DBH p.Val492Met (c.1474G>A) pathogenic?

DBH p.Val492Met (c.1474G>A) is classified Uncertain significance in DBH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-02). AlphaMissense: likely benign (0.1472); Very rare (popmax 0.00768%, sas); Associated with Inborn genetic diseases.

What condition is associated with DBH p.Val492Met (c.1474G>A)?

DBH p.Val492Met (c.1474G>A) is associated with Inborn genetic diseases (ClinVar).

How common is DBH p.Val492Met (c.1474G>A) in the general population?

DBH p.Val492Met (c.1474G>A) is very rare (popmax 0.00768%, sas) (gnomAD).

What do computational predictors say about DBH p.Val492Met (c.1474G>A)?

AlphaMissense predicts likely benign (score 0.1472) — an in-silico prediction, not a clinical call.

DBH p.Val492Met

c.1474G>A · VCV3499754

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1472 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00768%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1472	likely benign
REVEL	0.333	indeterminate
SaProt	LLR -8.43	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.32	GERP -2.3
Regional constraint	o/e 1.00	unconstrained · MANE · 22 kb · p 0.96 · regional, not allelic
Overall
CADD	16.63	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 0.00768% South Asian · 7/91,088 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00186% 30/1,613,786 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00768%	13,013
Remaining individualsnot grpmax-eligible	0.0048%	20,828
European (non-Finnish)	0.00169%	59,002

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.Val492Met
Coding: c.1474G>A
MANE Select: NM_000787
Type: single nucleotide variant
Location: chr9:133656562 (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 492: a disulfide bond; a β-strand

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.Val492= Likely benign ★ 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-val492met (accessed [today's date]).

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