# NM_032575.3(GLIS2):c.1431C>T (p.Pro477=)

https://sugi.bio/variant/glis2-p-pro477

## Summary

**GLIS2 p.Pro477= (c.1431C>T)** is classified **Conflicting classifications of pathogenicity** in GLIS2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-11-19). Ultra-rare (popmax 0.0433%, nfe); Associated with nephronophthisis.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs150810544 · 4 submitters · 2 linked conditions · ultra-rare (popmax 0.0433%, nfe)

## For patients & families {#patients}

This is a change in the GLIS2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, and is linked to nephronophthisis.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Finland) |
| Clinical trials | 6 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | GLIS2 is a diagnostic-grade gene on 5 Genomics England panels |

**Commonly reported features of Nephronophthisis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Renal insufficiency — Frequent (79-30%)
- Anemia — Frequent (79-30%)
- Abnormality of retinal pigmentation — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000206/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GLIS2](https://sugi.bio/atlas/gene/GLIS2/) |
| Protein change (HGVS p.) | p.Pro477= |
| Coding change (HGVS c.) | c.1431C>T |
| MANE Select transcript | [NM_032575](https://www.ncbi.nlm.nih.gov/nuccore/NM_032575) |
| dbSNP | [rs150810544](https://www.ncbi.nlm.nih.gov/snp/rs150810544/) |
| Variant type | single nucleotide variant |
| Location | chr16:4337380-4337380 (GRCh38) |
| ClinVar | [VCV319224](https://www.ncbi.nlm.nih.gov/clinvar/variation/319224/) |

**All HGVS expressions:** `NC_000016.10:g.4337380C>T`, `NC_000016.9:g.4387381C>T`, `NG_016391.2:g.27620C>T`, `NM_001318918.2:c.1431C>T`, `NM_032575.3:c.1431C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -10.427, GERP -3.23 — fast-evolving / accelerated position
- CADD: **PHRED 0.279**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — this absence is genuinely unknown. Where a position sits between the lowest and the highest record the release holds for its gene, an absent score is a result and we state it as one; this position falls outside them, or the gene has no scored position at all, so that test did not reach here. It may lie outside the scored MANE transcript scope, or it may have been scored with all four deltas below Δ0.2 just past the last surviving record. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0433%** (nfe) · FAF95 0.0401% · FAF99 0.0389% · 507/1,171,586 in the highest group · 555/1,593,540 alleles overall — ultra-rare (popmax 0.0433%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0433% | 2,311 |
| Remaining individuals (not grpmax-eligible) | 0.0405% | 2,468 |
| African / African-American | 0.0147% | 6,781 |
| Finnish (not grpmax-eligible) | 0.00842% | 11,872 |
| Admixed American | 0.00514% | 19,465 |
| East Asian | 0.00456% | 21,916 |
| South Asian | 0.00227% | 43,976 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**GLIS2** population constraint: LOEUF 0.637, pLI 0.32698, missense-Z 0.10964. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **nephronophthisis 7** — Moderate (AR)

## Protein context {#protein}

Residue **477** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 55.47, 0% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of GLIS2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** GLIS2's established molecular role includes sequence-specific double-stranded DNA binding. p.Pro477= falls in the disordered region.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** sequence-specific double-stranded DNA binding.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-11-19.

**Submitter consensus:** conflicting (3 Likely benign, 1 Uncertain significance).

**Submission history:** 4 submissions (2018–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2024-03-29 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-19 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-03 |

## Associated conditions {#conditions}

[nephronophthisis](https://sugi.bio/atlas/disease/nephronophthisis/), [nephronophthisis 7](https://sugi.bio/atlas/disease/nephronophthisis-7/).

**Reported phenotype names (ClinVar):** Nephronophthisis, Nephronophthisis 7, GLIS2-related disorder, not specified, Juvenile Nephronophthisis, AllHighlyPenetrant, GLIS2-related condition.

## Similar variants {#similar}

Related GLIS2 variant pages (same residue, condition, or type): [GLIS2 p.Pro477Ser](/variant/glis2-p-pro477ser), [GLIS2 c.*1826C>T](/variant/glis2-c-star-1826c-t), [GLIS2 c.*916G>A](/variant/glis2-c-star-916g-a), [GLIS2 p.Ala19Val](/variant/glis2-p-ala19val), [GLIS2 p.Ala210Thr](/variant/glis2-p-ala210thr), [GLIS2 p.Ala360Thr](/variant/glis2-p-ala360thr), [GLIS2 p.Ala437Thr](/variant/glis2-p-ala437thr), [GLIS2 p.Arg102Cys](/variant/glis2-p-arg102cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 319224). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*