Is GLIS2 p.Val523= (c.1569G>A) pathogenic?

GLIS2 p.Val523= (c.1569G>A) is classified Conflicting classifications of pathogenicity in GLIS2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-31). Rare (popmax 0.636%, mid); Associated with nephronophthisis.

What condition is associated with GLIS2 p.Val523= (c.1569G>A)?

GLIS2 p.Val523= (c.1569G>A) is associated with nephronophthisis, nephronophthisis 7 (ClinVar).

How common is GLIS2 p.Val523= (c.1569G>A) in the general population?

GLIS2 p.Val523= (c.1569G>A) is rare (popmax 0.636%, mid) (gnomAD).

How is Nephronophthisis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

GLIS2 p.Val523=

c.1569G>A · rs371022001 · VCV319226

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.636%, mid)

Conditions

nephronophthisis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 1.6, phastCons 1
Overall
CADD	15.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.636% Middle Eastern · 38/5,972 alleles

Filtering AF 0.477% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.421%

Overall 0.0255% 397/1,557,774 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.636%	157
Ashkenazi Jewishnot grpmax-eligible	0.187%	534
South Asian	0.0583%	1,716
Remaining individualsnot grpmax-eligible	0.056%	1,786
Admixed American	0.0318%	3,149
European (non-Finnish)	0.0172%	5,814
African / African-American	0.00673%	14,853

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GLIS2
Protein: p.Val523=
Coding: c.1569G>A
MANE Select: NM_032575
dbSNP: rs371022001
Type: single nucleotide variant
Location: chr16:4337518 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI 0.33 (gnomAD)
Structure: AlphaFold pLDDT 55.47

Full GLIS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nephronophthisis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 7

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

GLIS2 c.*1826C>T Uncertain significance ★★ same condition
GLIS2 c.*916G>A Uncertain significance ★★ same condition
GLIS2 p.Ala19Val Uncertain significance ★★ ⚠ same condition
GLIS2 p.Ala210Thr Uncertain significance ★★ same condition
GLIS2 p.Ala360Thr Uncertain significance ★★ ⚠ same condition
GLIS2 p.Ala437Thr Uncertain significance ★★ ⚠ same condition
GLIS2 p.Arg102Cys Uncertain significance ★★ ⚠ same condition
GLIS2 p.Arg24Gln Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/glis2-p-val523 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown