HADH

Chr 4AR

hydroxyacyl-CoA dehydrogenase

Also known as: HAD, HADH1, HADHSC, HCDH, HHF4, MSCHAD, SCHAD

NCBI Gene: 3033ENSG00000138796UniProt: Q16836

This gene is a member of the 3-hydroxyacyl-CoA dehydrogenase gene family. The encoded protein functions in the mitochondrial matrix to catalyze the oxidation of straight-chain 3-hydroxyacyl-CoAs as part of the beta-oxidation pathway. Its enzymatic activity is highest with medium-chain-length fatty acids. Mutations in this gene cause one form of familial hyperinsulinemic hypoglycemia. The human genome contains a related pseudogene of this gene on chromosome 15. [provided by RefSeq, May 2010]

Primary Disease Associations & Inheritance

3-hydroxyacyl-CoA dehydrogenase deficiencyMIM #231530
AR
Hyperinsulinemic hypoglycemia, familial, 4MIM #609975
AR
UniProt3-alpha-hydroxyacyl-CoA dehydrogenase deficiency
387
ClinVar variants
45
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— HADH
🧬
Gene-Disease Validity (ClinGen)
obsolete hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
45 Pathogenic / Likely Pathogenic· 89 VUS of 387 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.00LOEUF
pLI 0.000
Z-score 1.57
OE 0.57 (0.34–1.00)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.53Z-score
OE missense 0.89 (0.78–1.01)
163 obs / 183.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.57 (0.34–1.00)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.89 (0.78–1.01)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.05
0≤1.21.6
LoF obs/exp: 9 / 15.7Missense obs/exp: 163 / 183.1Syn Z: -0.35

ClinVar Variant Classifications

387 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27
Likely Pathogenic18
VUS89
Likely Benign178
Benign24
Conflicting51
27
Pathogenic
18
Likely Pathogenic
89
VUS
178
Likely Benign
24
Benign
51
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
10
1
16
0
27
Likely Pathogenic
12
2
4
0
18
VUS
0
78
9
2
89
Likely Benign
0
2
96
80
178
Benign
0
1
23
0
24
Conflicting
—51
Total228414882387

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

HADH · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

HADH-related 3-hydroxyacyl-CoA dehydrogenase deficiency

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

3-hydroxyacyl-CoA dehydrogenase deficiency

MIM #231530

Molecular basis of disorder known

Autosomal recessive

Hyperinsulinemic hypoglycemia, familial, 4

MIM #609975

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — HADH
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genotype and phenotype correlations in 417 children with congenital hyperinsulinism.
Snider KE et al.·J Clin Endocrinol Metab
2013
Congenital Hyperinsulinism: Diagnosis and Treatment Update.
Demirbilek H et al.·J Clin Res Pediatr Endocrinol
2017Review
Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism.
Kapoor RR et al.·Eur J Endocrinol
2013Cohort
Congenital hyperinsulinism: recent updates on molecular mechanisms, diagnosis and management.
Giri D et al.·J Pediatr Endocrinol Metab
2021Review
Molecular mechanisms of congenital hyperinsulinism.
Rahman SA et al.·J Mol Endocrinol
2015Review
Comprehensive clinical and molecular characterization with long-term outcomes in 40 patients with congenital hyperinsulinism.
Yavas Abali Z et al.·Endocrine
2025Cohort
Decreased expression of HADH is related to poor prognosis and immune infiltration in kidney renal clear cell carcinoma.
Jiang H et al.·Genomics
2021
Congenital hyperinsulinism due to mutations in HNF4A and HADH.
Kapoor RR et al.·Rev Endocr Metab Disord
2010Review
Congenital Hyperinsulinemic Hypoglycemia With a New HADH Mutation and Pancreatic Overexpression of GLP-1 Receptors.
Widmer A et al.·J Clin Endocrinol Metab
2026Case report
Unveiling ammonia-induced cell death: a new frontier in clear cell renal cell carcinoma prognosis.
Yu P et al.·Front Immunol
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools