# NM_173551.5(ANKS6):c.1690C>T (p.Pro564Ser)

https://sugi.bio/variant/anks6-p-pro564ser

## Summary

**ANKS6 p.Pro564Ser (c.1690C>T)** is classified **Uncertain significance** in ANKS6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-05). AlphaMissense: ambiguous (0.5296); Very rare (popmax 0.00409%, afr); Associated with nephronophthisis 16.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 0.00409%, afr)

## For patients & families {#patients}

This is a change in the ANKS6 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Pro564Ser |
| Coding change (HGVS c.) | c.1690C>T |
| MANE Select transcript | [NM_173551](https://www.ncbi.nlm.nih.gov/nuccore/NM_173551) |
| Variant type | single nucleotide variant |
| Location | chr9:98774008-98774008 (GRCh38) |
| ClinVar | [VCV3596051](https://www.ncbi.nlm.nih.gov/clinvar/variation/3596051/) |

**All HGVS expressions:** `NC_000009.11:g.101536290G>A`, `NC_000009.12:g.98774008G>A`, `NG_042237.1:g.27535C>T`, `NM_173551.5:c.1690C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL calls this damaging; SaProt does not; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.5296) — no call either way
- REVEL 0.668 (pathogenic-leaning)
- SaProt LLR -5.903 (tolerated)
- → **In-silico consensus:** REVEL calls this damaging; SaProt does not; AlphaMissense makes no call
- Conservation: phyloP 9.61, GERP 2.18, phastCons 1 — highly conserved
- CADD: **PHRED 26.8**. 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.*
- Regional missense constraint: **o/e 0.99** across the covering region of the MANE Select transcript (98,736,522–98,796,491), spanning 59,969 bp. Chi-square p 0.79. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.27 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00409%** (afr) · FAF95 0.00109% · FAF99 0.000501% · 3/73,384 in the highest group · 4/1,583,180 alleles overall — very rare (popmax 0.00409%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00409% | 24,461 |
| European (non-Finnish) | 8.58e-05% | 1,165,801 |

*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}


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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-05.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-01-05 |

## 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.Pro564Ala](/variant/anks6-p-pro564ala), [ANKS6 p.Pro564Thr](/variant/anks6-p-pro564thr), [ANKS6 c.1973-3C>G](/variant/anks6-c-1973-minus-3c-g), [ANKS6 p.Arg461Ter](/variant/anks6-p-arg461ter), [ANKS6 c.907+6C>T](/variant/anks6-c-907-plus-6c-t), [ANKS6 p.Ala215Thr](/variant/anks6-p-ala215thr), [ANKS6 p.Ala215Val](/variant/anks6-p-ala215val), [ANKS6 p.Ala249Thr](/variant/anks6-p-ala249thr).

### 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 3596051). 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.*