GPAA1

Chr 8AR

glycosylphosphatidylinositol anchor attachment 1

Also known as: GAA1, GPIBD15, hGAA1

NCBI Gene: 8733 ENSG00000197858 UniProt: O43292 OMIM: 603048

The protein is a component of the GPI-anchor transamidase complex that catalyzes the linkage between proteins and GPI anchors, enabling proteins to attach to cell surface membranes. Mutations cause glycosylphosphatidylinositol biosynthesis defect 15, which follows autosomal recessive inheritance. This gene is highly intolerant to loss-of-function variants (pLI near 1), indicating that complete loss of function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Posttranslational glycosylphosphatidylinositol (GPI) anchor attachment serves as a general mechanism for linking proteins to the cell surface membrane. The protein encoded by this gene presumably functions in GPI anchoring at the GPI transfer step. The mRNA transcript is ubiquitously expressed in both fetal and adult tissues. The anchor attachment protein 1 contains an N-terminal signal sequence, 1 cAMP- and cGMP-dependent protein kinase phosphorylation site, 1 leucine zipper pattern, 2 potential N-glycosylation sites, and 8 putative transmembrane domains. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.981 OMIM phenotype

Clinical Summary— GPAA1

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Gene-Disease Validity (ClinGen)

glycosylphosphatidylinositol biosynthesis defect 15 · 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

49 unique Pathogenic / Likely Pathogenic· 267 VUS of 649 total submissions

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?

0.98LOEUF

pLI 0.000

Z-score 1.65

OE 0.65 (0.45–0.98)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.87Z-score

OE missense 0.87 (0.80–0.96)

324 obs / 371.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.65 (0.45–0.98)

0≤0.351.4

Missense OE?0.87 (0.80–0.96)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 17 / 26.1Missense obs/exp: 324 / 371.1Syn Z: -0.43

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongGPAA1-related developmental delay, epilepsy, cerebellar atrophy, and osteopeniaLOFAR

This gene — mechanism propensity

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

0.7036th %ile

GOF

0.6834th %ile

LOF

0.2874th %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

649 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic24

Likely Pathogenic25

VUS267

Likely Benign297

Benign13

Conflicting9

Pathogenic

Likely Pathogenic

267

VUS

297

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	22	1	1	0	24
Likely Pathogenic	20	5	0	0	25
VUS	4	249	12	2	267
Likely Benign	0	5	108	184	297
Benign	0	3	5	5	13
Conflicting	—				9
Total	46	263	126	191	635

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

View in ClinVar →

61 pathogenic / likely-pathogenic (of 73) ClinVar copy-number / structural variants overlap GPAA1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →