Is GLIS2 p.Arg34Cys (c.100C>T) pathogenic?

GLIS2 p.Arg34Cys (c.100C>T) is classified Uncertain significance in GLIS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-12). AlphaMissense: ambiguous (0.3749); Very rare (popmax 0.00686%, nfe); Associated with nephronophthisis.

What condition is associated with GLIS2 p.Arg34Cys (c.100C>T)?

GLIS2 p.Arg34Cys (c.100C>T) is associated with nephronophthisis, nephronophthisis 7 (ClinVar).

How common is GLIS2 p.Arg34Cys (c.100C>T) in the general population?

GLIS2 p.Arg34Cys (c.100C>T) is very rare (popmax 0.00686%, nfe) (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.Arg34Cys (c.100C>T)?

AlphaMissense predicts ambiguous (score 0.3749) — an in-silico prediction, not a clinical call.

GLIS2 p.Arg34Cys

c.100C>T · rs369113794 · VCV1416713

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3749 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00686%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.3749	ambiguous
REVEL	0.124	moderately benign-leaning
SaProt	LLR -8.10	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.7	GERP 1.1, phastCons 0.99
Regional constraint	o/e 0.94	unconstrained · MANE · 2,809 bp · p 0.37 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00686% European (non-Finnish) · 81/1,180,026 alleles

Filtering AF 0.00563% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.00546% 88/1,612,884 alleles · very rare exomes 83/1,460,660 · genomes 5/152,224 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00686%	14,568
Remaining individualsnot grpmax-eligible	0.0064%	15,614
Admixed American	0.00333%	30,001
African / African-American	0.00133%	74,924

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.Arg34Cys
Coding: c.100C>T
MANE Select: NM_032575
dbSNP: rs369113794
Type: single nucleotide variant
Location: chr16:4332380 (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

Also linked: nephronophthisis 7

For Nephronophthisis (Orphanet):

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

Similar variants

GLIS2 p.Arg34His Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-arg34cys (accessed [today's date]).

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