Is GLIS3 p.Ser856= (c.2568G>A) pathogenic?

GLIS3 p.Ser856= (c.2568G>A) is classified Conflicting classifications of pathogenicity in GLIS3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-10). Ultra-rare (popmax 0.0233%, amr); Associated with neonatal diabetes mellitus with congenital hypothyroidism.

What condition is associated with GLIS3 p.Ser856= (c.2568G>A)?

GLIS3 p.Ser856= (c.2568G>A) is associated with neonatal diabetes mellitus with congenital hypothyroidism (ClinVar).

How common is GLIS3 p.Ser856= (c.2568G>A) in the general population?

GLIS3 p.Ser856= (c.2568G>A) is ultra-rare (popmax 0.0233%, amr) (gnomAD).

GLIS3 p.Ser856=

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.2568G>A · rs773065162 · VCV914326

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0233%, amr)

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 2.6	GERP -1.1, phastCons 1
Overall
CADD	11.53	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0233% Admixed American · 14/60,006 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0118%

Overall 0.0125% 201/1,613,990 alleles · ultra-rare exomes 197/1,461,838 · genomes 4/152,152 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0233%	4,286
Middle Eastern	0.0164%	6,084
European (non-Finnish)	0.0143%	6,982
Remaining individualsnot grpmax-eligible	0.0128%	7,810
South Asian	0.00659%	15,181
East Asian	0.00446%	22,443
African / African-American	0.00134%	74,890

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.Ser856=
Coding: c.2568G>A
MANE Select: NM_001042413
dbSNP: rs773065162
Type: single nucleotide variant
Location: chr9:3829398 (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

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

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

GLIS3 p.Ser856Trp 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-ser856 (accessed [today's date]).

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