Is GLIS3 p.Arg614= (c.1842C>T) pathogenic?

GLIS3 p.Arg614= (c.1842C>T) is classified Conflicting classifications of pathogenicity in GLIS3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-12-16). Rare (popmax 0.258%, mid); Associated with neonatal diabetes mellitus with congenital hypothyroidism.

What condition is associated with GLIS3 p.Arg614= (c.1842C>T)?

GLIS3 p.Arg614= (c.1842C>T) is associated with neonatal diabetes mellitus with congenital hypothyroidism (ClinVar).

How common is GLIS3 p.Arg614= (c.1842C>T) in the general population?

GLIS3 p.Arg614= (c.1842C>T) is rare (popmax 0.258%, mid) (gnomAD).

GLIS3 p.Arg614=

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.1842C>T · rs758753292 · VCV912867

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.258%, mid)

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 -2.2	GERP -4.2
Overall
CADD	5.871	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.258% Middle Eastern · 14/5,428 alleles

Filtering AF 0.156% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.125%

Overall 0.00335% 54/1,613,212 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.258%	388
Remaining individualsnot grpmax-eligible	0.0128%	7,798
African / African-American	0.00401%	24,969
East Asian	0.00223%	44,892
European (non-Finnish)	0.0022%	45,385
South Asian	0.0022%	45,521

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.Arg614=
Coding: c.1842C>T
MANE Select: NM_001042413
dbSNP: rs758753292
Type: single nucleotide variant
Location: chr9:3937058 (GRCh38)
Gene constraint: LOEUF 0.853 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 49.95
Residue 614: 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-arg614 (accessed [today's date]).

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