PNPLA1

Chr 6AR

patatin like domain 1, omega-hydroxyceramide transacylase

Also known as: ARCI10, dJ50J22.1

NCBI Gene: 285848ENSG00000180316UniProt: Q8N8W4

The protein encoded by this gene belongs to the patatin-like phospholipase (PNPLA) family, which is characterized by the presence of a highly conserved patatin domain. PNPLA family members have diverse lipolytic and acyltransferase activities, and are key elements in lipid metabolism. While other members of this family have been well characterized, the function of this gene remained an enigma. However, recent studies show that this gene is expressed in the skin epidermal keratinocytes, and has a role in glycerophospholipid metabolism in the cutaneous barrier. Consistent with these observations, mutations in this gene are associated with ichthyosis in human (autosomal recessive congenital ichthyoses, ARCI) and dog. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2012]

Primary Disease Associations & Inheritance

Ichthyosis, congenital, autosomal recessive 10MIM #615024
AR
279
ClinVar variants
57
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— PNPLA1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
57 Pathogenic / Likely Pathogenic· 115 VUS of 279 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.
0.75LOEUF
pLI 0.000
Z-score 2.47
OE 0.44 (0.27–0.75)
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.
0.73Z-score
OE missense 0.88 (0.80–0.98)
283 obs / 320.0 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.0.44 (0.27–0.75)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.88 (0.80–0.98)
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.1.09
0≤1.21.6
LoF obs/exp: 10 / 22.7Missense obs/exp: 283 / 320.0Syn Z: -0.82

ClinVar Variant Classifications

279 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27
Likely Pathogenic30
VUS115
Likely Benign45
Benign38
Conflicting24
27
Pathogenic
30
Likely Pathogenic
115
VUS
45
Likely Benign
38
Benign
24
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
4
11
12
0
27
Likely Pathogenic
9
17
4
0
30
VUS
1
99
11
4
115
Likely Benign
0
11
11
23
45
Benign
0
8
27
3
38
Conflicting
—24
Total141466530279

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

View in ClinVar →

Protein Context — Lollipop Plot

PNPLA1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

PNPLA1-related congenital ichthyosis

strong
ARUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Ichthyosis, congenital, autosomal recessive 10

MIM #615024

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — PNPLA1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The First Reported Japanese Case of PNPLA1-Nonsyndromic Epidermal Differentiation Disorder (PNPLA1-nEDD) Associated With an Unreported 92-Base-Pair Duplication Variant.
Kato S et al.·Exp Dermatol
2025Case report
Novel Pathogenic Mutation of PNPLA1 Identified in Autosomal Recessive Congenital Ichthyosis: A Case Report.
Li H et al.·Chin Med Sci J
2022Case report
Impairment of lipophagy by PNPLA1 mutations causes lipid droplet accumulation in primary fibroblasts of Autosomal Recessive Congenital Ichthyosis patients.
Onal G et al.·J Dermatol Sci
2019Cohort
Targeted regions sequencing identified four novel PNPLA1 mutations in two Chinese families with autosomal recessive congenital ichthyosis.
Li L et al.·Mol Genet Genomic Med
2020
Meta-Analysis of Mutations in ALOX12B or ALOXE3 Identified in a Large Cohort of 224 Patients.
Hotz A et al.·Genes (Basel)
2021Meta-analysis
[Analysis of PNPLA1 gene mutation in a child with ichthyosis].
Li H et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2020
Genotype-phenotype correlation in a large English cohort of patients with autosomal recessive ichthyosis.
Simpson JK et al.·Br J Dermatol
2020Cohort
Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses: Association of Genotype with Disease Severity, Phenotypic, and Ultrastructural Features in 74 Italian Patients.
Diociaiuti A et al.·Dermatology
2024Cohort
Novel and Recurrent PNPLA1 Mutations in Spanish Patients with Autosomal Recessive Congenital Ichthyosis; Evidence of a Founder Effect.
Esperón-Moldes U et al.·Acta Derm Venereol
2019Cohort
Genotype of autosomal recessive congenital ichthyosis from a tertiary care center in India.
Chiramel MJ et al.·Pediatr Dermatol
2022
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
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