# NM_173551.5(ANKS6):c.1683_1698dup (p.Phe567fs)

https://sugi.bio/variant/anks6-p-phe567fs

## Summary

**ANKS6 p.Phe567fs (c.1683_1698dup)** is classified **Pathogenic** in ANKS6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-04). No gnomAD frequency available for this variant; Associated with nephronophthisis 16.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2490390282 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ANKS6 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to nephronophthisis 16.

*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) |
| Diagnostic panels | ANKS6 is a diagnostic-grade gene on 10 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/0018183/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ANKS6](https://sugi.bio/atlas/gene/ANKS6/) |
| Protein change (HGVS p.) | p.Phe567fs |
| Coding change (HGVS c.) | c.1683_1698dup |
| MANE Select transcript | [NM_173551](https://www.ncbi.nlm.nih.gov/nuccore/NM_173551) |
| dbSNP | [rs2490390282](https://www.ncbi.nlm.nih.gov/snp/rs2490390282/) |
| Variant type | Duplication |
| Location | chr9:98773999-98774000 (GRCh38) |
| ClinVar | [VCV2883386](https://www.ncbi.nlm.nih.gov/clinvar/variation/2883386/) |

**All HGVS expressions:** `NC_000009.11:g.101536283_101536298dup`, `NC_000009.12:g.98774001_98774016dup`, `NG_042237.1:g.27528_27543dup`, `NM_173551.5:c.1683_1698dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 10.903, GERP 2.18, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.869, pLI 4.1775e-10. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 9 of 15**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**ANKS6** population constraint: LOEUF 0.869, pLI 4.1775e-10, missense-Z -0.7649; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *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 16** — Definitive (AR)

## Protein context {#protein}

Residue **567** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 60.60, 25% of residues very-high.

**1 experimental structure(s)** (PDB): [4NL9](https://www.rcsb.org/structure/4NL9).

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-12-04.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-12-04 |

## Associated conditions {#conditions}

[nephronophthisis 16](https://sugi.bio/atlas/disease/nephronophthisis-16/).

**Reported phenotype names (ClinVar):** Nephronophthisis 16.

## Similar variants {#similar}

Related ANKS6 variant pages (same residue, condition, or type): [ANKS6 p.Phe567=](/variant/anks6-p-phe567), [ANKS6 c.2327-19dup](/variant/anks6-c-2327-minus-19dup), [ANKS6 p.Asn218fs](/variant/anks6-p-asn218fs), [ANKS6 p.Gln504fs](/variant/anks6-p-gln504fs), [ANKS6 p.Gly122fs](/variant/anks6-p-gly122fs), [ANKS6 p.Pro559fs](/variant/anks6-p-pro559fs), [ANKS6 p.Thr808fs](/variant/anks6-p-thr808fs), [ANKS6 p.Val160fs](/variant/anks6-p-val160fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 2883386). 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.*