Is GLIS3 p.Arg32Pro (c.95G>C) pathogenic?

GLIS3 p.Arg32Pro (c.95G>C) is classified Uncertain significance in GLIS3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-01-20). Very rare (popmax 0.00492%, nfe); Associated with neonatal diabetes mellitus with congenital hypothyroidism.

How common is GLIS3 p.Arg32Pro (c.95G>C) in the general population?

GLIS3 p.Arg32Pro (c.95G>C) is very rare (popmax 0.00492%, nfe) (gnomAD).

GLIS3 p.Arg32Pro

Q: What condition is associated with GLIS3 p.Arg32Pro (c.95G>C)?

GLIS3 p.Arg32Pro (c.95G>C) is associated with neonatal diabetes mellitus with congenital hypothyroidism, monogenic diabetes (ClinVar).

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.95G>C · rs375834888 · VCV917457

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00492%, 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.
REVEL	0.208	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.064	GERP -2.2, phastCons 0.54
Regional constraint	o/e 1.38	unconstrained · MANE · 458 kb · p 3.1e-41 · regional, not allelic
Overall
CADD	19.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00492% European (non-Finnish) · 58/1,180,026 alleles

Filtering AF 0.00386% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00353%

Overall 0.00359% 58/1,614,060 alleles · very rare exomes 56/1,461,860 · genomes 2/152,200 · joint denominator

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.Arg32Pro
Coding: c.95G>C
MANE Select: NM_001042413
dbSNP: rs375834888
Type: single nucleotide variant
Location: chr9:4286331 (GRCh38)
Gene constraint: LOEUF 0.853 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 49.95

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

Also linked: monogenic diabetes

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

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

GLIS3 p.Arg32Gly Uncertain significance ★ same residue
GLIS3 p.Arg32Ter Conflicting classifications of pathogenicity ★ same residue
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

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-arg32pro (accessed [today's date]).

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