Is GLIS3 p.Pro124Ser (c.370C>T) pathogenic?

GLIS3 p.Pro124Ser (c.370C>T) is classified Uncertain significance in GLIS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-25). Very rare (popmax 0.0011%, sas); Associated with Inborn genetic diseases.

What condition is associated with GLIS3 p.Pro124Ser (c.370C>T)?

GLIS3 p.Pro124Ser (c.370C>T) is associated with Inborn genetic diseases (ClinVar).

How common is GLIS3 p.Pro124Ser (c.370C>T) in the general population?

GLIS3 p.Pro124Ser (c.370C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

GLIS3 p.Pro124Ser

c.370C>T · VCV4264224

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.04	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP 0.9, phastCons 1
Regional constraint	o/e 1.38	unconstrained · MANE · 458 kb · p 3.1e-41 · regional, not allelic
Overall
CADD	16.16	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,054 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000372% 6/1,613,858 alleles · very rare exomes 6/1,461,572 · genomes 0/152,286 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,480
South Asiangrpmax	0.0011%	91,054
European (non-Finnish)	0.000339%	294,973

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro124Ser
Coding: c.370C>T
MANE Select: NM_001042413
Type: single nucleotide variant
Location: chr9:4286056 (GRCh38)
Gene constraint: LOEUF 0.853 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 49.95
Residue 124: the 'disordered' region

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

Similar variants

GLIS3 p.Ala233Thr Uncertain significance ★★ ⚠ same condition
GLIS3 p.Ala784Pro Uncertain significance ★★ ⚠ same condition
GLIS3 p.Arg637Cys Uncertain significance ★★ ⚠ same condition
GLIS3 p.Arg663Gln Uncertain significance ★★ ⚠ same condition
GLIS3 p.Asp310Asn Uncertain significance ★★ ⚠ same condition
GLIS3 p.Cys676Phe Uncertain significance ★★ same condition
GLIS3 p.Gly385Ser Uncertain significance ★★ ⚠ same condition
GLIS3 p.Gly491Arg 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-pro124ser (accessed [today's date]).

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