ABHD12

Chr 20AR

abhydrolase domain containing 12, lysophospholipase

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

NCBI Gene: 26090ENSG00000100997UniProt: Q8N2K0

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]

Primary Disease Associations & Inheritance

Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataractMIM #612674
AR
664
ClinVar variants
80
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— ABHD12
🧬
Gene-Disease Validity (ClinGen)
PHARC syndrome · 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
80 Pathogenic / Likely Pathogenic· 283 VUS of 664 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.
0.76LOEUF
pLI 0.000
Z-score 2.47
OE 0.47 (0.30–0.76)
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.
0.19Z-score
OE missense 0.96 (0.86–1.08)
210 obs / 218.1 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.0.47 (0.30–0.76)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.96 (0.86–1.08)
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.1.01
0≤1.21.6
LoF obs/exp: 12 / 25.5Missense obs/exp: 210 / 218.1Syn Z: -0.07

ClinVar Variant Classifications

664 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic55
Likely Pathogenic25
VUS283
Likely Benign221
Benign51
Conflicting29
55
Pathogenic
25
Likely Pathogenic
283
VUS
221
Likely Benign
51
Benign
29
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
15
2
38
0
55
Likely Pathogenic
14
2
9
0
25
VUS
5
225
48
5
283
Likely Benign
0
3
132
86
221
Benign
0
3
43
5
51
Conflicting
—29
Total3423527096664

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

View in ClinVar →

Protein Context — Lollipop Plot

ABHD12 · protein map & ClinVar variants

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

Gene2Phenotype Curations

ABHD12-related polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract

definitive
ARLoss Of FunctionAbsent Gene Product
EyeEar
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract

MIM #612674

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — ABHD12
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Comprehensive Molecular Screening in Chinese Usher Syndrome Patients.
Sun T et al.·Invest Ophthalmol Vis Sci
2018Cohort
PHARC syndrome: an overview.
Harutyunyan L et al.·Orphanet J Rare Dis
2024Review
A novel ABHD12 nonsense variant in Usher syndrome type 3 family with genotype-phenotype spectrum review.
Li T et al.·Gene
2019Review
Genotype-phenotype spectrum and correlation of PHARC Syndrome due to pathogenic ABHD12 variants.
Long X et al.·BMC Med Genomics
2024
Genetic insights into PHARC syndrome: identification of a novel frameshift mutation in ABHD12.
Daneshi A et al.·BMC Med Genomics
2023
Tumor-Derived RAB21+ABHD12+ sEVs Drive the Premetastatic Microenvironment in the Lung.
Wu K et al.·Cancer Immunol Res
2024
Mendelian non-syndromic and syndromic hearing loss genes contribute to presbycusis.
Cornejo-Sanchez DM et al.·Eur J Hum Genet
2025
Genotype-phenotype correlation in a novel ABHD12 mutation underlying PHARC syndrome.
Thimm A et al.·J Peripher Nerv Syst
2020Case report
Whole-exome sequencing prioritizes candidate genes for hereditary cataract in the Emory mouse mutant.
Bennett TM et al.·G3 (Bethesda)
2023Functional
A complex homozygous mutation in ABHD12 responsible for PHARC syndrome discovered with NGS and review of the literature.
Lerat J et al.·J Peripher Nerv Syst
2017Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Case Report: novel GUCA1B and ABHD12 mutations in retinitis pigmentosa sine pigmento: expanding the genotypic spectrum through multimodal phenotyping.
Wu Y et al.·Front Med (Lausanne)
2025🔓 Open AccessCase report
Suppressing phagocyte activation by overexpressing the phosphatidylserine lipase ABHD12 preserves sarmopathic nerves.
Dingwall CB et al.·iScience
2025🔓 Open Access
Bioinformatics Analysis Identifies Sequence Determinants of Enzymatic Activity for the PHARC-Associated Lipase ABHD12.
Chakraborty A et al.·Biochemistry
2025
A Novel Compound Heterozygous Variant in the ABHD12 Gene Cause PHARC Syndrome in a Chinese Family: The Proband Presenting New Genotype and Phenotype.
Ma M et al.·Mol Genet Genomic Med
2025🔓 Open Access
Generation of a human iPSC line (UCLi025-A) from a patient with PHARC syndrome harbouring biallelic variants in ABHD12.
Romero-Vázquez S et al.·Stem Cell Res
2025
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