Is GLIS2 p.Asp80Val (c.239A>T) pathogenic?

GLIS2 p.Asp80Val (c.239A>T) is classified Conflicting classifications of pathogenicity in GLIS2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-22). AlphaMissense: likely pathogenic (0.8915); Rare (popmax 0.164%, mid); Associated with nephronophthisis.

What condition is associated with GLIS2 p.Asp80Val (c.239A>T)?

GLIS2 p.Asp80Val (c.239A>T) is associated with nephronophthisis, nephronophthisis 7 (ClinVar).

How common is GLIS2 p.Asp80Val (c.239A>T) in the general population?

GLIS2 p.Asp80Val (c.239A>T) is rare (popmax 0.164%, mid) (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.Asp80Val (c.239A>T)?

AlphaMissense predicts likely pathogenic (score 0.8915) — an in-silico prediction, not a clinical call.

GLIS2 p.Asp80Val

c.239A>T · rs144447862 · VCV195389

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.8915 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.164%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.8915	likely pathogenic
REVEL	0.161	moderately benign-leaning
SaProt	LLR -9.32	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 2,809 bp · p 0.37 · regional, not allelic
Overall
CADD	24.1	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 0.164% Middle Eastern · 10/6,084 alleles

Filtering AF 0.0891% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0678%

Overall 0.0545% 879/1,612,468 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.503%	199
Middle Easterngrpmax	0.164%	608
Remaining individualsnot grpmax-eligible	0.0993%	1,008
European (non-Finnish)	0.0521%	1,919
Admixed American	0.0434%	2,306
South Asian	0.0121%	8,277
African / African-American	0.00803%	12,455

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp80Val
Coding: c.239A>T
MANE Select: NM_032575
dbSNP: rs144447862
Type: single nucleotide variant
Location: chr16:4333413 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI 0.33 (gnomAD)
Structure: AlphaFold pLDDT 55.47
Residue 80: the 'interaction with ctnnd1' region; the 'transcription activation' region

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 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-asp80val (accessed [today's date]).

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