Is GLIS3 p.Pro445= (c.1335C>A) pathogenic?

GLIS3 p.Pro445= (c.1335C>A) is classified Likely benign in GLIS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-17). Ultra-rare (popmax 0.0889%, sas).

How common is GLIS3 p.Pro445= (c.1335C>A) in the general population?

GLIS3 p.Pro445= (c.1335C>A) is ultra-rare (popmax 0.0889%, sas) (gnomAD).

GLIS3 p.Pro445=

c.1335C>A · rs560316000 · VCV2179740

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0889%, sas)

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 -13	GERP -3.2
Overall
CADD	0.003	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0889% South Asian · 72/81,012 alleles

Filtering AF 0.0723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0663%

Overall 0.00478% 74/1,548,934 alleles · ultra-rare exomes 68/1,396,704 · genomes 6/152,230 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0889%	1,125
Remaining individualsnot grpmax-eligible	0.00336%	29,749

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.Pro445=
Coding: c.1335C>A
MANE Select: NM_001042413
dbSNP: rs560316000
Type: single nucleotide variant
Location: chr9:4118143 (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.Pro445Ala Uncertain significance ★ ⚠ same residue
GLIS3 p.Pro445His 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

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-pro445 (accessed [today's date]).

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