Is GLIS2 p.Arg34His (c.101G>A) pathogenic?

GLIS2 p.Arg34His (c.101G>A) is classified Conflicting classifications of pathogenicity in GLIS2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-11-21). AlphaMissense: likely benign (0.2257); Ultra-rare (popmax 0.0633%, amr); Associated with nephronophthisis.

What condition is associated with GLIS2 p.Arg34His (c.101G>A)?

GLIS2 p.Arg34His (c.101G>A) is associated with nephronophthisis, nephronophthisis 7 (ClinVar).

How common is GLIS2 p.Arg34His (c.101G>A) in the general population?

GLIS2 p.Arg34His (c.101G>A) is ultra-rare (popmax 0.0633%, amr) (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.Arg34His (c.101G>A)?

AlphaMissense predicts likely benign (score 0.2257) — an in-silico prediction, not a clinical call.

GLIS2 p.Arg34His

c.101G>A · rs377037409 · VCV568178

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2257 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0633%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.2257	likely benign
REVEL	0.026	moderately benign-leaning
SaProt	LLR -7.41	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 5.1	GERP 1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 2,809 bp · p 0.37 · regional, not allelic
Overall
CADD	19.68	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 0.0633% Admixed American · 38/60,020 alleles

Filtering AF 0.0474% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0418%

Overall 0.00428% 69/1,612,996 alleles · ultra-rare exomes 61/1,460,676 · genomes 8/152,320 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0633%	1,579
Middle Eastern	0.0165%	6,056
African / African-American	0.0133%	7,504
Remaining individualsnot grpmax-eligible	0.0032%	31,244
European (non-Finnish)	0.00153%	65,557

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.Arg34His
Coding: c.101G>A
MANE Select: NM_032575
dbSNP: rs377037409
Type: single nucleotide variant
Location: chr16:4332381 (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.Arg34Cys Uncertain significance ★★ ⚠ 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-arg34his (accessed [today's date]).

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