ABHD12

Chr 20AR

abhydrolase domain containing 12, lysophospholipase

Also known as: ABHD12A, BEM46L2, C20orf22, PHARC, dJ965G21.2, hABHD12

NCBI Gene: 26090 ENSG00000100997 UniProt: Q8N2K0 OMIM: 613599

The protein encoded by this gene is a lysophosphatidylserine lipase that hydrolyzes signaling lipids regulating neurological processes and also degrades the endocannabinoid 2-arachidonoylglycerol. Mutations cause PHARC syndrome (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract), a multisystem neurodegenerative disorder with autosomal recessive inheritance. The gene shows relatively high tolerance to loss-of-function variants (LOEUF 0.763), suggesting complete loss of function may be required for disease manifestation.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes an enzyme that catalyzes the hydrolysis of 2-arachidonoyl glycerol (2-AG), the main endocannabinoid lipid transmitter that acts on cannabinoid receptors, CB1 and CB2. The endocannabinoid system is involved in a wide range of physiological processes, including neurotransmission, mood, appetite, pain appreciation, addiction behavior, and inflammation. Mutations in this gene are associated with the neurodegenerative disease, PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract), resulting from an inborn error of endocannabinoid metabolism. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.[provided by RefSeq, Jan 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.761 OMIM phenotype

Clinical Summary— ABHD12

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Gene-Disease Validity (ClinGen)

PHARC syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

58 unique Pathogenic / Likely Pathogenic· 269 VUS of 640 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ABHD12

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?

0.76LOEUF

pLI 0.000

Z-score 2.47

OE 0.47 (0.30–0.76)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.19Z-score

OE missense 0.96 (0.86–1.08)

210 obs / 218.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.47 (0.30–0.76)

0≤0.351.4

Missense OE?0.96 (0.86–1.08)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 12 / 25.5Missense obs/exp: 210 / 218.1Syn Z: -0.07

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveABHD12-related polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataractLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6937th %ile

GOF

0.5856th %ile

LOF

0.2777th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

640 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic37

Likely Pathogenic21

VUS269

Likely Benign221

Benign51

Conflicting30

Pathogenic

Likely Pathogenic

269

VUS

221

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	29	2	6	0	37
Likely Pathogenic	17	3	1	0	21
VUS	6	226	32	5	269
Likely Benign	0	3	132	86	221
Benign	0	3	43	5	51
Conflicting	—				30
Total	52	237	214	96	629

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

View in ClinVar →

22 pathogenic / likely-pathogenic (of 36) ClinVar copy-number / structural variants overlap ABHD12 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →