HACD2

Chr 3

3-hydroxyacyl-CoA dehydratase 2

Also known as: PTPLB

NCBI Gene: 201562 ENSG00000206527 UniProt: Q6Y1H2 OMIM: 615939

The protein catalyzes the dehydration step in very long-chain fatty acid elongation within the endoplasmic reticulum, producing VLCFAs that serve as precursors for membrane lipids and lipid mediators. Mutations cause autosomal recessive congenital myopathy with fiber-type disproportion, affecting muscle development and function. The gene shows moderate tolerance to loss-of-function variants (LOEUF 0.74).

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene can catalyze the third step (dehydration) in the conversion of long chain fatty acids to very long chain fatty acids. The encoded protein localizes to the endoplasmic reticulum membrane. [provided by RefSeq, Jul 2016]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.74

Clinical Summary— HACD2

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 21 VUS of 29 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.74LOEUF

pLI 0.070

Z-score 2.20

OE 0.32 (0.16–0.74)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.86Z-score

OE missense 0.51 (0.42–0.64)

60 obs / 116.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.32 (0.16–0.74)

0≤0.351.4

Missense OE?0.51 (0.42–0.64)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 4 / 12.3Missense obs/exp: 60 / 116.7Syn Z: 0.46

This gene — mechanism propensity

0.6552th %ile

GOF

0.6443th %ile

LOF

0.3163th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction 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

29 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS21

Likely Benign1

Pathogenic

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Total
Pathogenic	0	1	1
Likely Pathogenic	0	0	0
VUS	20	1	21
Likely Benign	1	0	1
Benign	0	0	0
Total	21	2	23

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap HACD2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →