Is GLIS3 p.Pro418= (c.1254G>A) pathogenic?

GLIS3 p.Pro418= (c.1254G>A) is classified Likely benign in GLIS3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-12-16). Very rare (popmax 0.000171%, nfe); Associated with GLIS3-related disorder.

What condition is associated with GLIS3 p.Pro418= (c.1254G>A)?

GLIS3 p.Pro418= (c.1254G>A) is associated with GLIS3-related disorder (ClinVar).

How common is GLIS3 p.Pro418= (c.1254G>A) in the general population?

GLIS3 p.Pro418= (c.1254G>A) is very rare (popmax 0.000171%, nfe) (gnomAD).

GLIS3 p.Pro418=

c.1254G>A · rs1260550223 · VCV3061644

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000171%, nfe)

Conditions

GLIS3-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -14	GERP -3.7
Overall
CADD	0.104	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000171% European (non-Finnish) · 2/1,166,588 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000126% 2/1,586,222 alleles · very rare exomes 2/1,433,942 · genomes 0/152,280 · joint denominator

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.Pro418=
Coding: c.1254G>A
MANE Select: NM_001042413
dbSNP: rs1260550223
Type: single nucleotide variant
Location: chr9:4118224 (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

GLIS3-related disorder

Similar variants

GLIS3 p.Pro418Gln Uncertain significance ★ ⚠ same residue
GLIS3 c.*5T>C Likely benign same condition
GLIS3 p.Ser337= Likely benign same condition
GLIS3 c.596+6A>C Uncertain significance ★★ same type
GLIS3 c.*3330G>A Uncertain significance ★★ same type
GLIS3 c.*3344T>A Uncertain significance ★★ same type
GLIS3 c.*3920G>A Uncertain significance ★★ same type
GLIS3 c.*69T>C Uncertain significance ★★ same type

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-pro418 (accessed [today's date]).

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