Is GLIS3 p.Pro127= (c.381T>A) pathogenic?

GLIS3 p.Pro127= (c.381T>A) is classified Uncertain significance in GLIS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-30). Absent from gnomAD v4.1; Associated with neonatal diabetes mellitus with congenital hypothyroidism.

What condition is associated with GLIS3 p.Pro127= (c.381T>A)?

GLIS3 p.Pro127= (c.381T>A) is associated with neonatal diabetes mellitus with congenital hypothyroidism (ClinVar).

How common is GLIS3 p.Pro127= (c.381T>A) in the general population?

GLIS3 p.Pro127= (c.381T>A) is absent from gnomAD v4.1 (gnomAD).

GLIS3 p.Pro127=

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.381T>A · VCV3597447

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 0.97	GERP -3.7, phastCons 0.99
Overall
CADD	6.244	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GLIS3
Protein: p.Pro127=
Coding: c.381T>A
MANE Select: NM_001042413
Type: single nucleotide variant
Location: chr9:4286045 (GRCh38)
Gene constraint: LOEUF 0.853 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 49.95
Residue 127: 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 p.Pro127Leu Uncertain significance ★★ 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
GLIS3 p.Ala446Val 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-pro127 (accessed [today's date]).

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