Is GLIS3 p.Pro835= (c.2505C>G) pathogenic?

GLIS3 p.Pro835= (c.2505C>G) is classified Likely benign in GLIS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-18). Very rare (popmax 0.000763%, nfe).

How common is GLIS3 p.Pro835= (c.2505C>G) in the general population?

GLIS3 p.Pro835= (c.2505C>G) is very rare (popmax 0.000763%, nfe) (gnomAD).

GLIS3 p.Pro835=

c.2505C>G · VCV4797081

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.25	acceptor gain, 31 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -0.78	GERP -3.7
Overall
CADD	3.451	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000763% European (non-Finnish) · 9/1,180,022 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,614,016 alleles · very rare exomes 7/1,461,846 · genomes 2/152,170 · 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.Pro835=
Coding: c.2505C>G
MANE Select: NM_001042413
Type: single nucleotide variant
Location: chr9:3829461 (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

Similar variants

GLIS3 p.Pro835Ala Uncertain significance ★★ ⚠ same residue
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
GLIS3 p.Ala233Thr Uncertain significance ★★ ⚠ same type
GLIS3 p.Ala446Val 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-pro835 (accessed [today's date]).

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