Is DBH p.Val253Ile (c.757G>A) pathogenic?

DBH p.Val253Ile (c.757G>A) is classified Conflicting classifications of pathogenicity in DBH (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-03-23). AlphaMissense: likely benign (0.0595); Very rare (popmax 0.008%, afr); Associated with Inborn genetic diseases.

What condition is associated with DBH p.Val253Ile (c.757G>A)?

DBH p.Val253Ile (c.757G>A) is associated with Inborn genetic diseases, orthostatic hypotension 1 (ClinVar).

How common is DBH p.Val253Ile (c.757G>A) in the general population?

DBH p.Val253Ile (c.757G>A) is very rare (popmax 0.008%, afr) (gnomAD).

What do computational predictors say about DBH p.Val253Ile (c.757G>A)?

AlphaMissense predicts likely benign (score 0.0595) — an in-silico prediction, not a clinical call.

DBH p.Val253Ile

c.757G>A · rs527742213 · VCV1378698

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0595 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.008%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0595	likely benign
REVEL	0.085	moderately benign-leaning
SaProt	LLR -4.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.45 · evaluated, not missing
Constraint at this position
Conservation	phyloP -2.5	GERP -2.7
Regional constraint	o/e 1.00	unconstrained · MANE · 22 kb · p 0.96 · regional, not allelic
Overall
CADD	0.047	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 0.008% African / African-American · 6/74,986 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00228%

Overall 0.00285% 46/1,613,752 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.008%	12,498
East Asian	0.00669%	14,955
Admixed American	0.00333%	30,002
European (non-Finnish)	0.00297%	33,714

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.Val253Ile
Coding: c.757G>A
MANE Select: NM_000787
dbSNP: rs527742213
Type: single nucleotide variant
Location: chr9:133643425 (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 253: 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-val253ile (accessed [today's date]).

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