PIGV

Chr 1AR

phosphatidylinositol glycan anchor biosynthesis class V

Also known as: GPI-MT-II, HPMRS1, PIG-V

NCBI Gene: 55650 ENSG00000060642 UniProt: Q9NUD9 OMIM: 610274

The protein is a mannosyltransferase enzyme localized to the endoplasmic reticulum that transfers the second mannose to the glycosylphosphatidylinositol (GPI) backbone during GPI biosynthesis, where GPI serves as a membrane anchor for many proteins. Autosomal recessive mutations cause hyperphosphatasia with impaired intellectual development syndrome 1 through loss of function. The pathogenic mechanism involves disrupted GPI anchor biosynthesis leading to defective protein anchoring to cell membranes.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a mannosyltransferase enzyme involved in the biosynthesis of glycosylphosphatidylinositol (GPI). GPI is a complex glycolipid that functions as a membrane anchor for many proteins and plays a role in multiple cellular processes including protein sorting and signal transduction. The encoded protein is localized to the endoplasmic reticulum and transfers the second mannose to the GPI backbone. Mutations in this gene are associated with hyperphosphatasia cognitive disability syndrome. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Feb 2011]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.241 OMIM phenotype

Clinical Summary— PIGV

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Gene-Disease Validity (ClinGen)

hyperphosphatasia with intellectual disability syndrome 1 · ARModerate

Moderate evidence — consider for supplementary testing

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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

10 unique Pathogenic / Likely Pathogenic· 210 VUS of 395 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?

1.24LOEUF

pLI 0.000

Z-score 0.81

OE 0.79 (0.52–1.24)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.40Z-score

OE missense 0.93 (0.84–1.03)

240 obs / 258.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.79 (0.52–1.24)

0≤0.351.4

Missense OE?0.93 (0.84–1.03)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 14 / 17.7Missense obs/exp: 240 / 258.0Syn Z: 0.20

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePIGV-related hyperphosphatasia with intellectual developmental disorderLOFAR

This gene — mechanism propensity

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

0.6743th %ile

GOF

0.5170th %ile

LOF

0.2969th %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

395 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic7

VUS210

Likely Benign138

Benign7

Conflicting25

Pathogenic

Likely Pathogenic

210

VUS

138

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	3	0	0	3
Likely Pathogenic	2	5	0	0	7
VUS	15	171	21	3	210
Likely Benign	0	4	16	118	138
Benign	0	0	7	0	7
Conflicting	—				25
Total	17	183	44	121	390

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

View in ClinVar →

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