Is GLIS2 p.Val348Ile (c.1042G>A) pathogenic?

GLIS2 p.Val348Ile (c.1042G>A) is classified Uncertain significance in GLIS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-24). AlphaMissense: likely benign (0.1181); Absent from gnomAD v4.1; Associated with nephronophthisis.

What condition is associated with GLIS2 p.Val348Ile (c.1042G>A)?

GLIS2 p.Val348Ile (c.1042G>A) is associated with nephronophthisis (ClinVar).

How common is GLIS2 p.Val348Ile (c.1042G>A) in the general population?

GLIS2 p.Val348Ile (c.1042G>A) is absent from gnomAD v4.1 (gnomAD).

How is Nephronophthisis inherited?

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

What do computational predictors say about GLIS2 p.Val348Ile (c.1042G>A)?

AlphaMissense predicts likely benign (score 0.1181) — an in-silico prediction, not a clinical call.

GLIS2 p.Val348Ile

c.1042G>A · rs2505615490 · VCV2099035

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1181 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.1181	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -6.41	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 0.84, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 624 bp · p 0.045 · regional, not allelic
Overall
CADD	16.47	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GLIS2
Protein: p.Val348Ile
Coding: c.1042G>A
MANE Select: NM_032575
dbSNP: rs2505615490
Type: single nucleotide variant
Location: chr16:4336991 (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 condition
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-val348ile (accessed [today's date]).

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