Is GLIS2 p.Leu488= (c.1464G>A) pathogenic?

GLIS2 p.Leu488= (c.1464G>A) is classified Benign/Likely benign in GLIS2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-14). Low-frequency (popmax 1.46%, afr); Associated with kidney disorder.

What condition is associated with GLIS2 p.Leu488= (c.1464G>A)?

GLIS2 p.Leu488= (c.1464G>A) is associated with kidney disorder, nephronophthisis 7, nephronophthisis (ClinVar).

How common is GLIS2 p.Leu488= (c.1464G>A) in the general population?

GLIS2 p.Leu488= (c.1464G>A) is low-frequency (popmax 1.46%, afr) (gnomAD).

GLIS2 p.Leu488=

c.1464G>A · rs149580171 · VCV462720

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.46%, afr)

Conditions

kidney 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 1.2	GERP -3.2, phastCons 1
Overall
CADD	11.47	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.46% African / African-American · 1,086/74,572 alleles

Filtering AF 1.38% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.36%

Overall 0.0755% 1,200/1,588,886 alleles · low-frequency exomes 552/1,436,612 · genomes 648/152,274 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.46%	69
Admixed American	0.0867%	1,153
Remaining individualsnot grpmax-eligible	0.078%	1,283
Middle Eastern	0.0331%	3,021
South Asian	0.008%	12,507
European (non-Finnish)	0.000599%	167,051

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: GLIS2
Protein: p.Leu488=
Coding: c.1464G>A
MANE Select: NM_032575
dbSNP: rs149580171
Type: single nucleotide variant
Location: chr16:4337413 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI 0.33 (gnomAD)
Structure: AlphaFold pLDDT 55.47

Full GLIS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

kidney disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 7 nephronophthisis

Similar variants

GLIS2 c.*1826C>T Uncertain significance ★★ same condition
GLIS2 c.*916G>A Uncertain significance ★★ same condition
GLIS2 p.Ala19Val Uncertain significance ★★ ⚠ same condition
GLIS2 p.Ala210Thr Uncertain significance ★★ same condition
GLIS2 p.Ala360Thr Uncertain significance ★★ ⚠ same condition
GLIS2 p.Ala437Thr Uncertain significance ★★ ⚠ same condition
GLIS2 p.Arg102Cys Uncertain significance ★★ ⚠ same condition
GLIS2 p.Arg24Gln 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/glis2-p-leu488 (accessed [today's date]).

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