HACL1

Chr 3

2-hydroxyacyl-CoA lyase 1

Also known as: 2-HPCL, HPCL, HPCL2, PHYH2

NCBI Gene: 26061ENSG00000131373UniProt: Q9UJ83OMIM: 604300

The protein is a peroxisomal enzyme that cleaves fatty acids during alpha-oxidation, particularly breaking down phytanic acid and other branched-chain fatty acids. Mutations cause autosomal recessive disorders including infantile refsum disease and isolated phytanic acid accumulation, affecting neurological development and function. The gene shows no constraint against loss-of-function variants, consistent with the recessive inheritance pattern of associated disorders.

GeneReviewsOMIMResearchSummary from RefSeq, UniProt
DNmechanismLOEUF 1.01
Clinical Summary— HACL1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
26 unique Pathogenic / Likely Pathogenic· 107 VUS of 178 total submissions
Explore recent and relevant literature in Research Assistant →
📖
GeneReview available — HACL1
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
1.01LOEUF
pLI 0.000
Z-score 1.53
OE 0.71 (0.50–1.01)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
-0.04Z-score
OE missense 1.01 (0.92–1.10)
321 obs / 318.8 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.71 (0.50–1.01)
0≤0.351.4
Missense OE1.01 (0.92–1.10)
0≤0.61.4
Synonymous OE0.99
0≤1.21.6
LoF obs/exp: 22 / 31.2Missense obs/exp: 321 / 318.8Syn Z: 0.06
DN
0.6939th %ile
GOF
0.5661th %ile
LOF
0.3163th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

178 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic25
Likely Pathogenic1
VUS107
Likely Benign15
Benign7
25
Pathogenic
1
Likely Pathogenic
107
VUS
15
Likely Benign
7
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
24
0
25
Likely Pathogenic
0
0
1
0
1
VUS
0
104
3
0
107
Likely Benign
0
7
4
4
15
Benign
0
2
3
2
7
Total0114356155

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

View in ClinVar →

Protein Context — Lollipop Plot

HACL1 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 3 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients