Is GLIS3 p.Pro63Ser (c.187C>T) pathogenic?

GLIS3 p.Pro63Ser (c.187C>T) is classified Uncertain significance in GLIS3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-01). Ultra-rare (popmax 0.024%, afr); Associated with Inborn genetic diseases.

What condition is associated with GLIS3 p.Pro63Ser (c.187C>T)?

GLIS3 p.Pro63Ser (c.187C>T) is associated with Inborn genetic diseases, neonatal diabetes mellitus with congenital hypothyroidism (ClinVar).

How common is GLIS3 p.Pro63Ser (c.187C>T) in the general population?

GLIS3 p.Pro63Ser (c.187C>T) is ultra-rare (popmax 0.024%, afr) (gnomAD).

GLIS3 p.Pro63Ser

c.187C>T · rs537067524 · VCV1803893

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.024%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.05	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.38	unconstrained · MANE · 458 kb · p 3.1e-41 · regional, not allelic
Overall
CADD	17.09	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.024% African / African-American · 18/75,066 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.0044% 71/1,614,216 alleles · ultra-rare exomes 54/1,461,888 · genomes 17/152,328 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.024%	4,170
East Asian	0.0111%	8,975
Remaining individualsnot grpmax-eligible	0.0064%	15,627
Admixed American	0.005%	20,007
European (non-Finnish)	0.00347%	28,782

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.Pro63Ser
Coding: c.187C>T
MANE Select: NM_001042413
dbSNP: rs537067524
Type: single nucleotide variant
Location: chr9:4286239 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neonatal diabetes mellitus with congenital hypothyroidism

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-pro63ser (accessed [today's date]).

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