PAFAH1B1

Chr 17

platelet activating factor acetylhydrolase 1b regulatory subunit 1

Also known as: LIS1, LIS2, MDCR, MDS, NudF, PAFAH

NCBI Gene: 5048 ENSG00000007168 UniProt: P43034

The protein functions as the non-catalytic alpha subunit of intracellular platelet-activating factor acetylhydrolase Ib, which catalyzes the removal of acetyl groups from platelet-activating factor and localizes to the cytoskeleton. Loss-of-function mutations cause lissencephaly 1 and subcortical laminar heterotopia through autosomal dominant inheritance, with deletions also associated with Miller-Dieker lissencephaly syndrome.

ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This locus was identified as encoding a gene that when mutated or lost caused the lissencephaly associated with Miller-Dieker lissencephaly syndrome. This gene encodes the non-catalytic alpha subunit of the intracellular Ib isoform of platelet-activating factor acteylhydrolase, a heterotrimeric enzyme that specifically catalyzes the removal of the acetyl group at the SN-2 position of platelet-activating factor (identified as 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine). Two other isoforms of intracellular platelet-activating factor acetylhydrolase exist: one composed of multiple subunits, the other, a single subunit. In addition, a single-subunit isoform of this enzyme is found in serum. [provided by RefSeq, Apr 2009]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.11

Clinical Summary— PAFAH1B1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.11LOEUF

pLI 1.000

Z-score 4.89

OE 0.00 (0.00–0.11)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

3.53Z-score

OE missense 0.35 (0.29–0.42)

81 obs / 232.3 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.11)

0≤0.351.4

Missense OE?0.35 (0.29–0.42)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 0 / 27.9Missense obs/exp: 81 / 232.3Syn Z: 0.91

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePAFAH1B1-related lissencephalyLOFAD

This gene — mechanism propensity

0.2898th %ile

GOF

0.2796th %ile

LOF

0.83top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · LOEUF 0.11 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFPAFAH1B1 haploinsufficiency disrupts GABA neurons and synaptic E/I balance in the dentate gyrus.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References