PGAP2

Chr 11

post-GPI attachment to proteins 2

Also known as: CWH43-N, FRAG1, HPMRS3, MRT17, MRT21

NCBI Gene: 27315 ENSG00000148985 UniProt: Q9UHJ9

The protein catalyzes fatty acid remodeling of glycosylphosphatidylinositol (GPI) anchors by replacing unsaturated acyl chains with saturated stearoyl chains, which is critical for proper integration of GPI-anchored proteins into lipid rafts. Mutations cause autosomal recessive hyperphosphatasia with impaired intellectual development syndrome 3, characterized by elevated alkaline phosphatase levels and intellectual disability. The gene is highly constrained against loss-of-function variation (pLI 0.93, LOEUF 0.36), indicating that complete loss of protein function is poorly tolerated.

ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene plays a role in the maturation of glycosylphosphatidylinositol (GPI) anchors on GPI-anchored proteins. Mutations in this gene are associated with an autosomal recessive syndrome characterized by hyperphosphatasia and intellectual disability. [provided by RefSeq, Jul 2017]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.36

Clinical Summary— PGAP2

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.93). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

17 unique Pathogenic / Likely Pathogenic· 73 VUS of 168 total submissions

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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

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.36LOEUF

pLI 0.935

Z-score 3.09

OE 0.08 (0.03–0.36)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.93Z-score

OE missense 0.82 (0.72–0.93)

168 obs / 205.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.08 (0.03–0.36)

0≤0.351.4

Missense OE?0.82 (0.72–0.93)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 1 / 13.1Missense obs/exp: 168 / 205.7Syn Z: -0.21

ClinVar Variant Classifications

168 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic11

VUS73

Likely Benign34

Benign19

Conflicting6

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	2	4	0	0	6
Likely Pathogenic	3	8	0	0	11
VUS	2	68	3	0	73
Likely Benign	1	25	4	4	34
Benign	1	1	17	0	19
Conflicting	—				6
Total	9	106	24	4	149

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

View in ClinVar →

20 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap PGAP2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →