PPT1

Chr 1AR

palmitoyl-protein thioesterase 1

Also known as: CLN1, INCL, PPT

NCBI Gene: 5538 ENSG00000131238 UniProt: P50897 OMIM: 600722

The protein removes thioester-linked fatty acyl groups from cysteine residues during lysosomal degradation of lipid-modified proteins. Mutations cause neuronal ceroid lipofuscinosis 1 (CLN1), also known as infantile neuronal ceroid lipofuscinosis, inherited in an autosomal recessive pattern. Disease results from loss of enzyme function leading to accumulation of lipofuscin-like material in lysosomes.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene is a small glycoprotein involved in the catabolism of lipid-modified proteins during lysosomal degradation. The encoded enzyme removes thioester-linked fatty acyl groups such as palmitate from cysteine residues. Defects in this gene are a cause of infantile neuronal ceroid lipofuscinosis 1 (CLN1, or INCL) and neuronal ceroid lipofuscinosis 4 (CLN4). Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Dec 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.891 OMIM phenotype

Clinical Summary— PPT1

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Gene-Disease Validity (ClinGen)

neuronal ceroid lipofuscinosis · 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

185 unique Pathogenic / Likely Pathogenic· 228 VUS of 788 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 →

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GeneReview available — PPT1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.89LOEUF

pLI 0.000

Z-score 1.94

OE 0.52 (0.32–0.89)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.03Z-score

OE missense 0.99 (0.87–1.13)

163 obs / 164.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.52 (0.32–0.89)

0≤0.351.4

Missense OE?0.99 (0.87–1.13)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 10 / 19.2Missense obs/exp: 163 / 164.2Syn Z: -1.10

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePPT1-related neuronal ceroid lipofuscinosisLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6551th %ile

GOF

0.5660th %ile

LOF

0.2385th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

788 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic73

Likely Pathogenic112

VUS228

Likely Benign292

Benign45

Conflicting30

Pathogenic

112

Likely Pathogenic

228

VUS

292

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	53	10	10	0	73
Likely Pathogenic	68	39	5	0	112
VUS	1	173	47	7	228
Likely Benign	1	0	149	142	292
Benign	0	3	42	0	45
Conflicting	—				30
Total	123	225	253	149	780

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 12) ClinVar copy-number / structural variants overlap PPT1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →