Is GLIS3 p.Pro40Arg (c.119C>G) pathogenic?

GLIS3 p.Pro40Arg (c.119C>G) is classified Uncertain significance in GLIS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-28). Very rare (popmax 0.00144%, nfe); Associated with Inborn genetic diseases.

What condition is associated with GLIS3 p.Pro40Arg (c.119C>G)?

GLIS3 p.Pro40Arg (c.119C>G) is associated with Inborn genetic diseases (ClinVar).

How common is GLIS3 p.Pro40Arg (c.119C>G) in the general population?

GLIS3 p.Pro40Arg (c.119C>G) is very rare (popmax 0.00144%, nfe) (gnomAD).

GLIS3 p.Pro40Arg

c.119C>G · rs367934659 · VCV2298221

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.121	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.38	unconstrained · MANE · 458 kb · p 3.1e-41 · regional, not allelic
Overall
CADD	19.23	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00144% European (non-Finnish) · 17/1,180,034 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.0013% 21/1,614,210 alleles · very rare exomes 21/1,461,882 · genomes 0/152,328 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,627
European (non-Finnish)grpmax	0.00144%	69,414

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.Pro40Arg
Coding: c.119C>G
MANE Select: NM_001042413
dbSNP: rs367934659
Type: single nucleotide variant
Location: chr9:4286307 (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

Similar variants

GLIS3 p.Pro40Leu Uncertain significance ★★ same residue
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

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-pro40arg (accessed [today's date]).

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