Is GLIS2 p.Ala19= (c.57G>A) pathogenic?

GLIS2 p.Ala19= (c.57G>A) is classified Likely benign in GLIS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-27). Ultra-rare (popmax 0.033%, mid); Associated with nephronophthisis.

What condition is associated with GLIS2 p.Ala19= (c.57G>A)?

GLIS2 p.Ala19= (c.57G>A) is associated with nephronophthisis (ClinVar).

How common is GLIS2 p.Ala19= (c.57G>A) in the general population?

GLIS2 p.Ala19= (c.57G>A) is ultra-rare (popmax 0.033%, mid) (gnomAD).

How is Nephronophthisis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

GLIS2 p.Ala19=

c.57G>A · rs199506809 · VCV2900055

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

nephronophthisis

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 4.4	GERP -0.23, phastCons 1
Overall
CADD	14.61	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00124% 20/1,613,246 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
Admixed American	0.02%	5,001
East Asian	0.00223%	44,892
European (non-Finnish)	0.000424%	236,003

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.Ala19=
Coding: c.57G>A
MANE Select: NM_032575
dbSNP: rs199506809
Type: single nucleotide variant
Location: chr16:4332337 (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

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

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

GLIS2 p.Ala19Val Uncertain significance ★★ ⚠ same residue
GLIS2 p.Ala210Thr Uncertain significance ★★ same condition
GLIS2 p.Ala360Thr Uncertain significance ★★ ⚠ same condition
GLIS2 p.Arg102Cys Uncertain significance ★★ ⚠ same condition
GLIS2 p.Arg332His Uncertain significance ★★ ⚠ same condition
GLIS2 p.Arg34Cys Uncertain significance ★★ ⚠ same condition
GLIS2 p.Asn414Asp Uncertain significance ★★ ⚠ same condition
GLIS2 p.Glu443Lys 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-ala19 (accessed [today's date]).

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