LPIN1

Chr 2AR

lipin 1

Also known as: PAP1

NCBI Gene: 23175 ENSG00000134324 UniProt: Q14693 OMIM: 605518

This gene encodes a magnesium-ion-dependent phosphatidic acid phosphohydrolase enzyme that catalyzes the penultimate step in triglyceride synthesis including the dephosphorylation of phosphatidic acid to yield diacylglycerol. Expression of this gene is required for adipocyte differentiation and it also functions as a nuclear transcriptional coactivator with some peroxisome proliferator-activated receptors to modulate expression of other genes involved in lipid metabolism. Mutations in this gene are associated with metabolic syndrome, type 2 diabetes, acute recurrent rhabdomyolysis, and autosomal recessive acute recurrent myoglobinuria (ARARM). This gene is also a candidate for several human lipodystrophy syndromes. [provided by RefSeq, Mar 2017]

OMIM Research

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.731 OMIM phenotype

Clinical Summary— LPIN1

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Gene-Disease Validity (ClinGen)

myoglobinuria, acute recurrent, autosomal recessive · 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

62 unique Pathogenic / Likely Pathogenic· 348 VUS of 880 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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?

0.73LOEUF

pLI 0.000

Z-score 3.19

OE 0.53 (0.40–0.73)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.87Z-score

OE missense 0.90 (0.83–0.96)

499 obs / 556.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.53 (0.40–0.73)

0≤0.351.4

Missense OE?0.90 (0.83–0.96)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 29 / 54.4Missense obs/exp: 499 / 556.7Syn Z: 0.15

This gene — mechanism propensity

0.6842th %ile

GOF

0.5465th %ile

LOF

0.3648th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction 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

880 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic38

Likely Pathogenic24

VUS348

Likely Benign325

Benign88

Conflicting38

Pathogenic

Likely Pathogenic

348

VUS

325

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	31	1	6	0	38
Likely Pathogenic	20	2	1	1	24
VUS	6	275	65	2	348
Likely Benign	0	6	158	161	325
Benign	0	5	78	5	88
Conflicting	—				38
Total	57	289	308	169	861

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

View in ClinVar →

22 pathogenic / likely-pathogenic (of 35) ClinVar copy-number / structural variants overlap LPIN1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →