Is GLIS3 p.Ser424Pro (c.1270T>C) pathogenic?

GLIS3 p.Ser424Pro (c.1270T>C) is classified Benign in GLIS3 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0582); Common (popmax 100%, mid) — too common for a highly-penetrant pathogenic allele; Associated with neonatal diabetes mellitus with congenital hypothyroidism.

What condition is associated with GLIS3 p.Ser424Pro (c.1270T>C)?

GLIS3 p.Ser424Pro (c.1270T>C) is associated with neonatal diabetes mellitus with congenital hypothyroidism (ClinVar).

What do computational predictors say about GLIS3 p.Ser424Pro (c.1270T>C)?

AlphaMissense predicts likely benign (score 0.0582) — an in-silico prediction, not a clinical call.

GLIS3 p.Ser424Pro

Q: How common is GLIS3 p.Ser424Pro (c.1270T>C) in the general population?

GLIS3 p.Ser424Pro (c.1270T>C) is common (popmax 100%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.1270T>C · rs806052 · VCV129159

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0582 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 100%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neonatal diabetes mellitus with congenital hypothyroidism

Computational evidence

Protein change
AlphaMissense	0.0582	likely benign
REVEL	0.003	strongly benign-leaning
SaProt	LLR -5.56	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 0.063	GERP -4.1, phastCons 0.043
Regional constraint	o/e 1.38	unconstrained · MANE · 458 kb · p 3.1e-41 · regional, not allelic
Overall
CADD	1.622	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S269P vs ClinVar S424P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 100% Middle Eastern · 5,756/5,756 alleles

Filtering AF 99.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 99.8%

Overall 100% 1,584,712/1,585,008 alleles · common exomes 1,432,543/1,432,684 · genomes 152,169/152,324 · joint denominator

Ancestry group	Frequency	1 in
East Asian	100%	1
South Asian	100%	1
Ashkenazi Jewishnot grpmax-eligible	100%	1
Amishnot grpmax-eligible	100%	1
Middle Easterngrpmax	100%	1
European (non-Finnish)	100%	1
Finnishnot grpmax-eligible	100%	1
Admixed American	100%	1
Remaining individualsnot grpmax-eligible	100%	1
African / African-American	99.6%	1

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.Ser424Pro
Coding: c.1270T>C
MANE Select: NM_001042413
dbSNP: rs806052
Type: single nucleotide variant
Location: chr9:4118208 (GRCh38)
Gene constraint: LOEUF 0.853 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 49.95
Residue 269 UniProt numbering: a UniProt-annotated variant site (in)

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.Ser424Leu Uncertain significance ★ ⚠ same residue
GLIS3 p.Ser424= Likely benign ★ 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-ser424pro (accessed [today's date]).

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