Is GLIS3 p.Ser893Phe (c.2678C>T) pathogenic?

GLIS3 p.Ser893Phe (c.2678C>T) is classified Uncertain significance in GLIS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-19). AlphaMissense: likely benign (0.299); Rare (popmax 0.216%, eas); Associated with neonatal diabetes mellitus with congenital hypothyroidism.

What condition is associated with GLIS3 p.Ser893Phe (c.2678C>T)?

GLIS3 p.Ser893Phe (c.2678C>T) is associated with neonatal diabetes mellitus with congenital hypothyroidism (ClinVar).

How common is GLIS3 p.Ser893Phe (c.2678C>T) in the general population?

GLIS3 p.Ser893Phe (c.2678C>T) is rare (popmax 0.216%, eas) (gnomAD).

What do computational predictors say about GLIS3 p.Ser893Phe (c.2678C>T)?

AlphaMissense predicts likely benign (score 0.299) — an in-silico prediction, not a clinical call.

GLIS3 p.Ser893Phe

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.2678C>T · VCV4078786

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.299 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.216%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neonatal diabetes mellitus with congenital hypothyroidism

Computational evidence

Protein change
AlphaMissense	0.299	likely benign
REVEL	0.204	benign-leaning
SaProt	LLR -9.02	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.38	unconstrained · MANE · 458 kb · p 3.1e-41 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S738F vs ClinVar S893F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.216% East Asian · 97/44,862 alleles

Filtering AF 0.181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.168%

Overall 0.00725% 117/1,613,484 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.216%	462
Remaining individualsnot grpmax-eligible	0.0208%	4,803
South Asian	0.00549%	18,211
European (non-Finnish)	0.000169%	590,012

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.Ser893Phe
Coding: c.2678C>T
MANE Select: NM_001042413
Type: single nucleotide variant
Location: chr9:3828387 (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 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-ser893phe (accessed [today's date]).

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