HACL1

Chr 3

2-hydroxyacyl-CoA lyase 1

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

NCBI Gene: 26061 ENSG00000131373 UniProt: Q9UJ83 OMIM: 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.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

Enables several functions, including 2-hydroxyacyl-CoA lyase activity; ATP binding activity; and cation binding activity. Involved in fatty acid alpha-oxidation; phytanic acid metabolic process; and protein targeting to peroxisome. Located in nucleoplasm and peroxisome. [provided by Alliance of Genome Resources, Jul 2025]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.01

Clinical Summary— HACL1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 104 VUS of 150 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — HACL1

Authoritative clinical overview · Recommended first read

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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 OE?0.71 (0.50–1.01)

0≤0.351.4

Missense OE?1.01 (0.92–1.10)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 22 / 31.2Missense obs/exp: 321 / 318.8Syn Z: 0.06

This gene — mechanism propensity

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

150 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

VUS104

Likely Benign14

Benign7

Pathogenic

104

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	1	0	2
Likely Pathogenic	0	0	0	0
VUS	104	0	0	104
Likely Benign	7	3	4	14
Benign	2	3	2	7
Total	114	7	6	127

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

View in ClinVar →

24 pathogenic / likely-pathogenic (of 28) ClinVar copy-number / structural variants overlap HACL1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →