Is GLIS3 p.Pro596= (c.1788G>A) pathogenic?

GLIS3 p.Pro596= (c.1788G>A) is classified Conflicting classifications of pathogenicity in GLIS3 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-01). Ultra-rare (popmax 0.0868%, nfe); Associated with neonatal diabetes mellitus with congenital hypothyroidism.

What condition is associated with GLIS3 p.Pro596= (c.1788G>A)?

GLIS3 p.Pro596= (c.1788G>A) is associated with neonatal diabetes mellitus with congenital hypothyroidism (ClinVar).

How common is GLIS3 p.Pro596= (c.1788G>A) in the general population?

GLIS3 p.Pro596= (c.1788G>A) is ultra-rare (popmax 0.0868%, nfe) (gnomAD).

GLIS3 p.Pro596=

Q: How is Neonatal diabetes-congenital hypothyroidism-congenital glaucoma-hepatic fibrosis-polycystic kidneys syndrome inherited?

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

c.1788G>A · rs150364458 · VCV912868

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0868%, nfe)

Conditions

neonatal diabetes mellitus with congenital hypothyroidism

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 -13	GERP -4.2
Overall
CADD	7.696	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0868% European (non-Finnish) · 1,024/1,180,024 alleles

Filtering AF 0.0823% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0806%

Overall 0.0717% 1,158/1,614,058 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.118%	845
European (non-Finnish)grpmax	0.0868%	1,152
Admixed American	0.0416%	2,401
African / African-American	0.0333%	3,002
East Asian	0.00891%	11,220
South Asian	0.00439%	22,769
Finnishnot grpmax-eligible	0.00312%	32,012

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: GLIS3
Protein: p.Pro596=
Coding: c.1788G>A
MANE Select: NM_001042413
dbSNP: rs150364458
Type: single nucleotide variant
Location: chr9:3937112 (GRCh38)
Gene constraint: LOEUF 0.853 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 49.95
Residue 596: the 'disordered' region

Full GLIS3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neonatal diabetes mellitus with congenital hypothyroidism — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Neonatal diabetes-congenital hypothyroidism-congenital glaucoma-hepatic fibrosis-polycystic kidneys syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

GLIS3 c.596+6A>C Uncertain significance ★★ same condition
GLIS3 c.*3330G>A Uncertain significance ★★ same condition
GLIS3 c.*3344T>A Uncertain significance ★★ same condition
GLIS3 c.*3920G>A Uncertain significance ★★ same condition
GLIS3 c.*69T>C Uncertain significance ★★ same condition
GLIS3 p.Ala233Thr Uncertain significance ★★ ⚠ same condition
GLIS3 p.Ala446Val Uncertain significance ★★ ⚠ same condition
GLIS3 p.Ala693Thr 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/glis3-p-pro596 (accessed [today's date]).

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