PGAP3

Chr 17

post-GPI attachment to proteins phospholipase 3

Also known as: AGLA546, CAB2, PERLD1, PP1498, hCOS16

NCBI Gene: 93210 ENSG00000161395 UniProt: Q96FM1

This gene encodes a GPI-specific phospholipase that removes unsaturated fatty acids from GPI anchors in the Golgi apparatus, which is critical for proper integration of GPI-anchored proteins into lipid rafts. Mutations cause hyperphosphatasia with impaired intellectual development syndrome 4, an autosomal recessive disorder characterized by cognitive disability and elevated alkaline phosphatase levels. The gene shows tolerance to loss-of-function variants (pLI 0.002, LOEUF 0.83), consistent with its recessive inheritance pattern.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a glycosylphosphatidylinositol (GPI)-specific phospholipase that primarily localizes to the Golgi apparatus. This ubiquitously expressed gene is predicted to encode a seven-transmembrane protein that removes unsaturated fatty acids from the sn-2 position of GPI. The remodeling of the constituent fatty acids on GPI is thought to be important for the proper association between GPI-anchored proteins and lipid rafts. The tethering of proteins to plasma membranes via posttranslational GPI-anchoring is thought to play a role in protein sorting and trafficking. Mutations in this gene cause an autosomal recessive form of neurologic hyperphosphatasia with cognitive disability (HPMRS4). Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2017]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.83

Clinical Summary— PGAP3

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Gene-Disease Validity (ClinGen)

hyperphosphatasia with intellectual disability syndrome 4 · 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

42 unique Pathogenic / Likely Pathogenic· 82 VUS of 250 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.83LOEUF

pLI 0.002

Z-score 2.05

OE 0.44 (0.25–0.83)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.69Z-score

OE missense 0.86 (0.75–0.98)

154 obs / 179.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.44 (0.25–0.83)

0≤0.351.4

Missense OE?0.86 (0.75–0.98)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 7 / 15.8Missense obs/exp: 154 / 179.9Syn Z: 0.67

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePGAP3-related hyperphosphatasia with intellectual developmental disorder syndromeLOFAR

This gene — mechanism propensity

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

0.7326th %ile

GOF

0.7126th %ile

LOF

0.2288th %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

250 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic26

Likely Pathogenic16

VUS82

Likely Benign89

Benign17

Conflicting9

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	18	6	2	0	26
Likely Pathogenic	10	5	1	0	16
VUS	0	80	1	1	82
Likely Benign	0	8	26	55	89
Benign	0	1	14	2	17
Conflicting	—				9
Total	28	100	44	58	239

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap PGAP3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →