GLIS1

Chr 1

GLIS family zinc finger 1

NCBI Gene: 148979 ENSG00000174332 UniProt: Q8NBF1 OMIM: 610378

The GLIS1 protein is a zinc finger transcription factor that both activates and represses gene expression, controlling cell differentiation by inhibiting lineage commitment of multipotent cells. Mutations cause nephronophthisis, an autosomal recessive cystic kidney disease that can progress to end-stage renal failure in childhood. The gene shows low constraint to loss-of-function variation (pLI 0.04, LOEUF 0.61), consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

GLIS1 is a GLI (MIM 165220)-related Kruppel-like zinc finger protein that functions as an activator and repressor of transcription (Kim et al., 2002 [PubMed 12042312]).[supplied by OMIM, Mar 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.61

Clinical Summary— GLIS1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.31) despite low pLI — interpret in context.

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ClinVar Variants

112 VUS of 130 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?

0.61LOEUF

pLI 0.039

Z-score 2.82

OE 0.31 (0.17–0.61)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.04Z-score

OE missense 0.99 (0.91–1.08)

360 obs / 362.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.31 (0.17–0.61)

0≤0.351.4

Missense OE?0.99 (0.91–1.08)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 6 / 19.4Missense obs/exp: 360 / 362.3Syn Z: 0.19

This gene — mechanism propensity

0.6937th %ile

GOF

0.5169th %ile

LOF

0.58top 25%

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

130 submitted variants in ClinVar

ClinVar

Classification Summary

VUS112

Likely Benign4

Benign6

Conflicting1

112

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	0	112	0	0	112
Likely Benign	0	2	0	2	4
Benign	0	3	1	2	6
Conflicting	—				1
Total	0	117	1	4	123

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap GLIS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →