GLIS2

Chr 16AR

GLIS family zinc finger 2

Also known as: NKL, NPHP7

NCBI Gene: 84662 ENSG00000126603 UniProt: Q9BZE0 OMIM: 608539

GLIS2 encodes a nuclear transcription factor with zinc finger domains that regulates gene expression in kidney morphogenesis and neuronal differentiation, particularly maintaining epithelial cell identity in renal tissues. Mutations cause nephronophthisis 7, an autosomal recessive kidney disease characterized by tubular basement membrane disruption, interstitial infiltration, and cyst development at the kidney's corticomedullary border. The gene is highly constrained against loss-of-function variants (pLI 0.86, LOEUF 0.42), indicating intolerance to protein-disrupting mutations.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene is a member of the GLI-similar zinc finger protein family and encodes a nuclear transcription factor with five C2H2-type zinc finger domains. The protein encoded by this gene is widely expressed at low levels in the neural tube and peripheral nervous system and likely promotes neuronal differentiation. It is abundantly expressed in the kidney and may have a role in the regulation of kidney morphogenesis. p120 regulates the expression level of this protein and induces the cleavage of this protein's C-terminal zinc finger domain. This protein also promotes the nuclear translocation of p120. Mutations in this gene cause nephronophthisis (NPHP), an autosomal recessive kidney disease characterized by tubular basement membrane disruption, interstitial lymphohistiocytic cell infiltration, and development of cysts at the corticomedullary border of the kidneys.[provided by RefSeq, Jan 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.411 OMIM phenotype

Clinical Summary— GLIS2

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Gene-Disease Validity (ClinGen)

nephronophthisis 7 · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.86) — some intolerance to loss-of-function variants.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 229 VUS of 360 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 →

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GeneReview available — GLIS2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.41LOEUF

pLI 0.858

Z-score 3.14

OE 0.13 (0.05–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.79Z-score

OE missense 0.88 (0.80–0.97)

290 obs / 330.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.13 (0.05–0.41)

0≤0.351.4

Missense OE?0.88 (0.80–0.97)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 2 / 15.2Missense obs/exp: 290 / 330.5Syn Z: -0.94

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongGLIS2-related nephronophthisisLOFAR

This gene — mechanism propensity

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

0.4784th %ile

GOF

0.3986th %ile

LOF

0.78top 5%

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

360 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS229

Likely Benign79

Benign22

Conflicting21

Pathogenic

229

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	0	0	1
Likely Pathogenic	0	0	0	0	0
VUS	6	167	45	11	229
Likely Benign	0	6	22	51	79
Benign	0	2	16	4	22
Conflicting	—				21
Total	7	175	83	66	352

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

View in ClinVar →

34 pathogenic / likely-pathogenic (of 45) ClinVar copy-number / structural variants overlap GLIS2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →