PIGL

Chr 17AR

phosphatidylinositol glycan anchor biosynthesis class L

Also known as: CHIME

NCBI Gene: 9487 ENSG00000108474 UniProt: Q9Y2B2 OMIM: 605947

The protein catalyzes the second step of glycosylphosphatidylinositol (GPI) biosynthesis by performing de-N-acetylation of N-acetylglucosaminylphosphatidylinositol in the endoplasmic reticulum. Mutations cause CHIME syndrome through an autosomal recessive inheritance pattern. The pathogenic mechanism appears to be dominant negative.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes an enzyme that catalyzes the second step of glycosylphosphatidylinositol (GPI) biosynthesis, which is the de-N-acetylation of N-acetylglucosaminylphosphatidylinositol (GlcNAc-PI). Study of a similar rat enzyme suggests that this protein localizes to the endoplasmic reticulum. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.511 OMIM phenotype

Clinical Summary— PIGL

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Gene-Disease Validity (ClinGen)

syndromic intellectual disability · 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

21 unique Pathogenic / Likely Pathogenic· 78 VUS of 161 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?

1.51LOEUF

pLI 0.000

Z-score 0.17

OE 0.95 (0.62–1.51)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.05Z-score

OE missense 0.99 (0.86–1.14)

146 obs / 147.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.95 (0.62–1.51)

0≤0.351.4

Missense OE?0.99 (0.86–1.14)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 13 / 13.7Missense obs/exp: 146 / 147.5Syn Z: -0.28

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePIGL-related coloboma, congenital heart disease, ichthyosiform dermatosis, impaired intellectual development, and ear anomalies syndrome (CHIME)LOFAR

This gene — mechanism propensity

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

0.6551th %ile

GOF

0.4974th %ile

LOF

0.3552th %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

161 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10

Likely Pathogenic11

VUS78

Likely Benign40

Benign10

Conflicting11

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	9	1	0	0	10
Likely Pathogenic	7	4	0	0	11
VUS	2	58	12	6	78
Likely Benign	2	10	17	11	40
Benign	0	0	10	0	10
Conflicting	—				11
Total	20	73	39	17	160

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

View in ClinVar →

25 pathogenic / likely-pathogenic (of 45) ClinVar copy-number / structural variants overlap PIGL — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →