Is GLIS2 p.Pro415= (c.1245G>A) pathogenic?

GLIS2 p.Pro415= (c.1245G>A) is classified Likely benign in GLIS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-12). Very rare (popmax 0.00548%, afr); Associated with nephronophthisis.

What condition is associated with GLIS2 p.Pro415= (c.1245G>A)?

GLIS2 p.Pro415= (c.1245G>A) is associated with nephronophthisis (ClinVar).

How common is GLIS2 p.Pro415= (c.1245G>A) in the general population?

GLIS2 p.Pro415= (c.1245G>A) is very rare (popmax 0.00548%, afr) (gnomAD).

How is Nephronophthisis inherited?

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

GLIS2 p.Pro415=

c.1245G>A · rs755435780 · VCV702293

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00548%, afr)

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 -2	GERP -3.5
Overall
CADD	3.654	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00548% African / African-American · 4/73,034 alleles

Filtering AF 0.00178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00153%

Overall 0.00226% 35/1,545,748 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00548%	18,259
European (non-Finnish)	0.00253%	39,551
East Asian	0.00244%	40,956
Admixed American	0.00196%	51,018

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.Pro415=
Coding: c.1245G>A
MANE Select: NM_032575
dbSNP: rs755435780
Type: single nucleotide variant
Location: chr16:4337194 (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

For Nephronophthisis (Orphanet):

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

Similar variants

GLIS2 p.Pro415Leu Uncertain significance ★★ ⚠ same residue
GLIS2 p.Ala19Val Uncertain significance ★★ ⚠ same condition
GLIS2 p.Ala210Thr Uncertain significance ★★ same condition
GLIS2 p.Ala360Thr Uncertain significance ★★ ⚠ same condition
GLIS2 p.Arg102Cys Uncertain significance ★★ ⚠ same condition
GLIS2 p.Arg332His Uncertain significance ★★ ⚠ same condition
GLIS2 p.Arg34Cys Uncertain significance ★★ ⚠ same condition
GLIS2 p.Asn414Asp 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-pro415 (accessed [today's date]).

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