# NM_173551.5(ANKS6):c.1827C>T (p.Pro609=)

https://sugi.bio/variant/anks6-p-pro609

## Summary

**ANKS6 p.Pro609= (c.1827C>T)** is classified **Likely benign** in ANKS6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-14). Ultra-rare (popmax 0.0339%, mid); Associated with nephronophthisis 16.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs377000748 · 3 submitters · 1 linked condition · ultra-rare (popmax 0.0339%, mid)

## For patients & families {#patients}

This is a change in the ANKS6 gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters, 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.Pro609= |
| Coding change (HGVS c.) | c.1827C>T |
| MANE Select transcript | [NM_173551](https://www.ncbi.nlm.nih.gov/nuccore/NM_173551) |
| dbSNP | [rs377000748](https://www.ncbi.nlm.nih.gov/snp/rs377000748/) |
| Variant type | single nucleotide variant |
| Location | chr9:98771041-98771041 (GRCh38) |
| ClinVar | [VCV2075640](https://www.ncbi.nlm.nih.gov/clinvar/variation/2075640/) |

**All HGVS expressions:** `NC_000009.11:g.101533323G>A`, `NC_000009.12:g.98771041G>A`, `NG_042237.1:g.30502C>T`, `NG_078896.1:g.315G>A`, `NM_173551.4:c.1827C>T`, `NM_173551.5:c.1827C>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 -7.015, GERP -4.76 — fast-evolving / accelerated position
- CADD: **PHRED 0.031**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.23 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 **0.0339%** (mid) · FAF95 0.00885% · FAF99 0.00828% · 2/5,906 in the highest group · 134/1,566,660 alleles overall — ultra-rare (popmax 0.0339%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0339% | 2,953 |
| African / African-American | 0.011% | 9,129 |
| European (non-Finnish) | 0.0104% | 9,635 |
| South Asian | 0.0024% | 41,630 |
| East Asian | 0.00237% | 42,226 |
| Remaining individuals (not grpmax-eligible) | 0.00165% | 60,496 |

*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 **609** 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-06-14.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2019–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-03-20 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-06-02 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-06-14 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Nephronophthisis 16, ANKS6-related disorder, not specified, AllHighlyPenetrant, ANKS6-related condition.

## Similar variants {#similar}

Related ANKS6 variant pages (same residue, condition, or type): [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), [ANKS6 p.Ala261Thr](/variant/anks6-p-ala261thr), [ANKS6 p.Ala350Thr](/variant/anks6-p-ala350thr).

### 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 2075640). 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.*