Is GLIS2 p.Pro520= (c.1560G>A) pathogenic?

GLIS2 p.Pro520= (c.1560G>A) is classified Uncertain significance in GLIS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-04). Very rare (popmax 0.00539%, afr); Associated with nephronophthisis 7.

What condition is associated with GLIS2 p.Pro520= (c.1560G>A)?

GLIS2 p.Pro520= (c.1560G>A) is associated with nephronophthisis 7 (ClinVar).

How common is GLIS2 p.Pro520= (c.1560G>A) in the general population?

GLIS2 p.Pro520= (c.1560G>A) is very rare (popmax 0.00539%, afr) (gnomAD).

How is Nephronophthisis inherited?

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

GLIS2 p.Pro520=

c.1560G>A · rs759274279 · VCV596805

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00539%, afr)

Conditions

nephronophthisis 7

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 -2.7	GERP -3.2
Overall
CADD	0.508	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00539% African / African-American · 4/74,226 alleles

Filtering AF 0.002% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00171%

Overall 0.00263% 41/1,560,656 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00539%	18,556
East Asian	0.00466%	21,469
European (non-Finnish)	0.00276%	36,197
South Asian	0.00233%	42,992
Admixed American	0.00185%	53,930

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.Pro520=
Coding: c.1560G>A
MANE Select: NM_032575
dbSNP: rs759274279
Type: single nucleotide variant
Location: chr16:4337509 (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 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Nephronophthisis (Orphanet):

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

Similar variants

GLIS2 p.Pro520Leu Uncertain significance ★★ ⚠ same residue
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.Ala437Thr Uncertain significance ★★ ⚠ same condition
GLIS2 p.Arg24Gln Uncertain significance ★★ ⚠ same condition
GLIS2 p.Arg332His 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-pro520 (accessed [today's date]).

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