Is GLIS3 p.Pro670= (c.2010A>G) pathogenic?

GLIS3 p.Pro670= (c.2010A>G) is classified Likely benign in GLIS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). Ultra-rare (popmax 0.055%, amr).

How common is GLIS3 p.Pro670= (c.2010A>G) in the general population?

GLIS3 p.Pro670= (c.2010A>G) is ultra-rare (popmax 0.055%, amr) (gnomAD).

GLIS3 p.Pro670=

c.2010A>G · rs367590913 · VCV2050490

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.055%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.79	GERP -5.4, phastCons 0.001
Overall
CADD	12.61	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.055% Admixed American · 33/60,014 alleles

Filtering AF 0.0402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0351%

Overall 0.0233% 376/1,614,130 alleles · ultra-rare exomes 351/1,461,880 · genomes 25/152,250 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.055%	1,819
Remaining individualsnot grpmax-eligible	0.0288%	3,473
European (non-Finnish)	0.0273%	3,665
African / African-American	0.00267%	37,514
East Asian	0.00223%	44,882

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.Pro670=
Coding: c.2010A>G
MANE Select: NM_001042413
dbSNP: rs367590913
Type: single nucleotide variant
Location: chr9:3898809 (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 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
GLIS3 p.Ala615Ser 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-pro670 (accessed [today's date]).

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