PHARC syndrome

Summary

PHARC syndrome (MONDO:0012984) is a disease caused by ABHD12 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ABHD12 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 78

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		19	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	PHARC syndrome
Mondo ID	MONDO:0012984
MeSH	C567203
OMIM	612674
Orphanet	171848
DOID	DOID:0080181
SNOMED CT	723452007
UMLS	C2675204
MedGen	436373
GARD	0017071
Is cancer (heuristic)	no

Also known as: peripheral neuropathy, Fiskerstrand type · PHARC · PHARC syndrome · polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract

Data availability: 78 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › PHARC syndrome

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

78 retrieved; paginated sample, class counts are floors:

24 uncertain significance, 16 benign, 16 pathogenic, 15 conflicting classifications of pathogenicity, 5 likely pathogenic, 1 likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1322604	NM_001042472.3(ABHD12):c.1015C>T (p.Gln339Ter)	ABHD12	Pathogenic	criteria provided, single submitter
1389869	NM_001042472.3(ABHD12):c.205_206del (p.Trp69fs)	ABHD12	Pathogenic	criteria provided, single submitter
143235	NM_001042472.3(ABHD12):c.1116C>G (p.His372Gln)	ABHD12	Pathogenic	no assertion criteria provided
143236	NM_001042472.3(ABHD12):c.477G>A (p.Trp159Ter)	ABHD12	Pathogenic	criteria provided, single submitter
1727244	NM_001042472.3(ABHD12):c.601dup (p.Val201fs)	ABHD12	Pathogenic	criteria provided, single submitter
24	NM_001042472.3(ABHD12):c.337_338delinsTTT (p.Asp113fs)	ABHD12	Pathogenic	criteria provided, single submitter
26	NM_001042472.3(ABHD12):c.846_852dup (p.His285Ter)	ABHD12	Pathogenic	no assertion criteria provided
27	NM_001042472.3(ABHD12):c.1054C>T (p.Arg352Ter)	ABHD12	Pathogenic	criteria provided, multiple submitters, no conflicts
3601008	NM_001042472.3(ABHD12):c.690G>A (p.Trp230Ter)	ABHD12	Pathogenic	criteria provided, single submitter
4087742	NM_001042472.3(ABHD12):c.134_137dup (p.Ala47fs)	ABHD12	Pathogenic	criteria provided, single submitter
430695	NM_001042472.3(ABHD12):c.211_223del (p.Arg71fs)	ABHD12	Pathogenic	criteria provided, single submitter
452247	NM_001042472.3(ABHD12):c.874C>T (p.Arg292Ter)	ABHD12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
518455	NM_001042472.3(ABHD12):c.249C>G (p.Tyr83Ter)	ABHD12	Pathogenic	criteria provided, single submitter
1684636	NC_000020.11:g.25387767_25393170del	LOC130065585	Pathogenic	criteria provided, single submitter
243081	Single allele	LOC130065585	Pathogenic	criteria provided, single submitter
25	NM_015600.4(ABHD12):c.-6898_191+7002delinsCC	LOC130065586	Pathogenic	no assertion criteria provided
4293842	NM_001042472.3(ABHD12):c.120dup (p.Arg41fs)	LOC130065586	Pathogenic	criteria provided, single submitter
1710109	NM_001042472.3(ABHD12):c.788-1G>T	ABHD12	Likely pathogenic	no assertion criteria provided
265985	NM_001042472.3(ABHD12):c.971C>T (p.Pro324Leu)	ABHD12	Likely pathogenic	no assertion criteria provided
438131	NM_001042472.3(ABHD12):c.620-2A>G	ABHD12	Likely pathogenic	no assertion criteria provided
545443	NM_001042472.3(ABHD12):c.1124_1129del (p.Ile375_Tyr376del)	ABHD12	Likely pathogenic	criteria provided, single submitter
3252004	NC_000020.11:g.25302218_25320318del	LOC130065580	Likely pathogenic	criteria provided, single submitter
143237	NM_001042472.3(ABHD12):c.557G>C (p.Arg186Pro)	ABHD12	Conflicting classifications of pathogenicity	no assertion criteria provided
191159	NM_001042472.3(ABHD12):c.1189C>T (p.Gln397Ter)	ABHD12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
283186	NM_001042472.3(ABHD12):c.1041C>T (p.Ile347=)	ABHD12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337991	NM_001042472.3(ABHD12):c.858A>C (p.Pro286=)	ABHD12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337992	NM_001042472.3(ABHD12):c.802G>T (p.Ala268Ser)	ABHD12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337993	NM_001042472.3(ABHD12):c.769C>T (p.Arg257Trp)	ABHD12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337994	NM_001042472.3(ABHD12):c.543-13T>C	ABHD12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
337995	NM_001042472.3(ABHD12):c.453C>T (p.Asn151=)	ABHD12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ABHD12	Definitive	Autosomal recessive	PHARC syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ABHD12	Orphanet:171848	Polyneuropathy-hearing loss-ataxia-retinitis pigmentosa-cataract syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ABHD12	HGNC:15868	ENSG00000100997	Q8N2K0	Lysophosphatidylserine lipase ABHD12	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ABHD12	Lysophosphatidylserine lipase ABHD12	Lysophosphatidylserine (LPS) lipase that mediates the hydrolysis of lysophosphatidylserine, a class of signaling lipids that regulates immunological and neurological processes.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ABHD12	Other/Unknown	no		AB_hydrolase_1, AB_hydrolase_fold

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
C1 segment of cervical spinal cord	1
prefrontal cortex	1
spinal cord	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ABHD12	256	ubiquitous	marker	C1 segment of cervical spinal cord, prefrontal cortex, spinal cord

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABHD12	1,296

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ABHD12	Q8N2K0	85.60

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Arachidonate production from DAG	1	2284.0×	0.004	ABHD12
Effects of PIP2 hydrolysis	1	456.8×	0.009	ABHD12
Platelet activation, signaling and aggregation	1	105.7×	0.025	ABHD12
G alpha (q) signalling events	1	57.4×	0.032	ABHD12
GPCR downstream signalling	1	43.4×	0.032	ABHD12
Signaling by GPCR	1	40.1×	0.032	ABHD12
Hemostasis	1	36.0×	0.032	ABHD12
Signal Transduction	1	10.2×	0.098	ABHD12

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
phosphatidylserine catabolic process	1	4213.0×	0.001	ABHD12
acylglycerol catabolic process	1	3370.4×	0.001	ABHD12
monoacylglycerol catabolic process	1	2407.4×	0.001	ABHD12
phospholipid catabolic process	1	1203.7×	0.002	ABHD12
glycerophospholipid catabolic process	1	1053.2×	0.002	ABHD12
response to auditory stimulus	1	732.7×	0.002	ABHD12
adult walking behavior	1	495.6×	0.002	ABHD12
arachidonate metabolic process	1	481.5×	0.002	ABHD12
regulation of inflammatory response	1	168.5×	0.006	ABHD12

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ABHD12	ORLISTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ABHD12	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ORLISTAT	4	ABHD12
DRONABINOL	4	ABHD12

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ABHD12	35	Binding:31, Toxicity:3, ADMET:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
ORLISTAT	4	ABHD12
DRONABINOL	4	ABHD12

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ABHD12
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.