Is GLIS2 p.Pro477= (c.1431C>T) pathogenic?

GLIS2 p.Pro477= (c.1431C>T) is classified Conflicting classifications of pathogenicity in GLIS2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-11-19). Ultra-rare (popmax 0.0433%, nfe); Associated with nephronophthisis.

What condition is associated with GLIS2 p.Pro477= (c.1431C>T)?

GLIS2 p.Pro477= (c.1431C>T) is associated with nephronophthisis, nephronophthisis 7 (ClinVar).

How common is GLIS2 p.Pro477= (c.1431C>T) in the general population?

GLIS2 p.Pro477= (c.1431C>T) is ultra-rare (popmax 0.0433%, nfe) (gnomAD).

How is Nephronophthisis inherited?

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

GLIS2 p.Pro477=

c.1431C>T · rs150810544 · VCV319224

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0433%, nfe)

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 -10	GERP -3.2
Overall
CADD	0.279	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0433% European (non-Finnish) · 507/1,171,586 alleles

Filtering AF 0.0401% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0389%

Overall 0.0348% 555/1,593,540 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0433%	2,311
Remaining individualsnot grpmax-eligible	0.0405%	2,468
African / African-American	0.0147%	6,781
Finnishnot grpmax-eligible	0.00842%	11,872
Admixed American	0.00514%	19,465
East Asian	0.00456%	21,916
South Asian	0.00227%	43,976

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.Pro477=
Coding: c.1431C>T
MANE Select: NM_032575
dbSNP: rs150810544
Type: single nucleotide variant
Location: chr16:4337380 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI 0.33 (gnomAD)
Structure: AlphaFold pLDDT 55.47
Residue 477: the 'disordered' region

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 p.Pro477Ser 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.Ala360Thr Uncertain significance ★★ ⚠ same condition
GLIS2 p.Ala437Thr Uncertain significance ★★ ⚠ same condition
GLIS2 p.Arg102Cys 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-pro477 (accessed [today's date]).

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