Is HADH p.Val53= (c.159A>G) pathogenic?

HADH p.Val53= (c.159A>G) is classified Conflicting classifications of pathogenicity in HADH (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-03-28). Very rare (popmax 0.00801%, afr); Associated with hyperinsulinemic hypoglycemia, familial, 4.

What condition is associated with HADH p.Val53= (c.159A>G)?

HADH p.Val53= (c.159A>G) is associated with hyperinsulinemic hypoglycemia, familial, 4, hyperinsulinemic hypoglycemia, 3-hydroxyacyl-CoA dehydrogenase deficiency (ClinVar).

How common is HADH p.Val53= (c.159A>G) in the general population?

HADH p.Val53= (c.159A>G) is very rare (popmax 0.00801%, afr) (gnomAD).

HADH p.Val53=

Q: How is Hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.159A>G · rs148846625 · VCV902149

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Conditions

hyperinsulinemic hypoglycemia, familial, 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.2	GERP -5
Overall
CADD	2.16	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00801% African / African-American · 6/74,882 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.000372% 6/1,612,446 alleles · very rare exomes 5/1,460,288 · genomes 1/152,158 · joint denominator

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: HADH
Protein: p.Val53=
Coding: c.159A>G
MANE Select: NM_005327
dbSNP: rs148846625
Type: single nucleotide variant
Location: chr4:108009785 (GRCh38)
Gene constraint: LOEUF 1.09 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.90 · 12 PDB
Residue 53: a β-strand

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

Disease context

hyperinsulinemic hypoglycemia, familial, 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hyperinsulinemic hypoglycemia 3-hydroxyacyl-CoA dehydrogenase deficiency

For Hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

HADH c.261+1G>A Pathogenic/Likely pathogenic ★★ same condition
HADH c.262-2A>G Likely pathogenic ★★ same condition
HADH c.709+2T>C Likely pathogenic ★★ same condition
HADH p.Arg236Ter Pathogenic/Likely pathogenic ★★ same condition
HADH p.Gly34Arg Likely pathogenic ★★ same condition
HADH p.Ala239Ser Uncertain significance ★★ ⚠ same condition
HADH p.Glu235Asp Uncertain significance ★★ ⚠ same condition
HADH p.Gly34Ser 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/hadh-p-val53 (accessed [today's date]).

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