# NM_014391.3(ANKRD1):c.617T>C (p.Leu206Pro)

https://sugi.bio/variant/ankrd1-p-leu206pro

## Summary

**ANKRD1 p.Leu206Pro (c.617T>C)** is classified **Uncertain significance** in ANKRD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-29). AlphaMissense: likely pathogenic (0.9904); Very rare (popmax 8.47e-05%, nfe); Associated with ANKRD1-related dilated cardiomyopathy.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1554827664 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the ANKRD1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to ANKRD1-related dilated cardiomyopathy.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ANKRD1](https://sugi.bio/atlas/gene/ANKRD1/) |
| Protein change (HGVS p.) | p.Leu206Pro |
| Coding change (HGVS c.) | c.617T>C |
| MANE Select transcript | [NM_014391](https://www.ncbi.nlm.nih.gov/nuccore/NM_014391) |
| dbSNP | [rs1554827664](https://www.ncbi.nlm.nih.gov/snp/rs1554827664/) |
| Variant type | single nucleotide variant |
| Location | chr10:90916205-90916205 (GRCh38) |
| ClinVar | [VCV543938](https://www.ncbi.nlm.nih.gov/clinvar/variation/543938/) |

**All HGVS expressions:** `LRG_379:g.10071T>C`, `LRG_379t1:c.617T>C`, `NC_000010.10:g.92675962A>G`, `NC_000010.11:g.90916205A>G`, `NG_023227.1:g.10071T>C`, `NM_014391.3:c.617T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9904)
- REVEL 0.887 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.664 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 9.39, GERP 1.17, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 3%** most-pathogenic-predicted substitutions in ANKRD1 (of 1,866 modeled).
- CADD: **PHRED 30.0**. 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 0.93** across the covering region of the MANE Select transcript (90,912,869–90,921,027), spanning 8,158 bp. Chi-square p 0.17. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,180,010 in the highest group · 1/152,074 alleles overall — very rare (popmax 8.47e-05%, nfe).

*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}

**ANKRD1** population constraint: LOEUF 1.038, pLI 7.6168e-09, missense-Z 0.80164. *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):

- **dilated cardiomyopathy** — Limited (AD)
- **hypertrophic cardiomyopathy** — Disputed (AD)
- **congenital heart disease** — Limited (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 82.64, 54% of residues very-high.

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

*Describes the biological roles of ANKRD1 (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:** ANKRD1's established molecular role includes p53 binding.


### Pathways affected {#pathways}

ANKRD1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [PPARA activates gene expression](https://reactome.org/content/detail/R-HSA-1989781) | curated |

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

**Molecular function:** p53 binding, DNA binding, transcription coactivator activity, titin binding, histone deacetylase binding, RNA polymerase II-specific DNA-binding transcription factor binding.

**Biological process:** response to muscle stretch, positive regulation of apoptotic process, positive regulation of DNA damage response, signal transduction by p53 class mediator, positive regulation of protein secretion, cardiac muscle tissue morphogenesis, cellular response to lipopolysaccharide.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-08-29.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-08-29 |

## Associated conditions {#conditions}

[ANKRD1-related dilated cardiomyopathy](https://sugi.bio/atlas/disease/ankrd1-related-dilated-cardiomyopathy/).

**Reported phenotype names (ClinVar):** ANKRD1-related dilated cardiomyopathy.

## Similar variants {#similar}

Related ANKRD1 variant pages (same residue, condition, or type): [ANKRD1 c.651+6C>T](/variant/ankrd1-c-651-plus-6c-t), [ANKRD1 c.652-2A>T](/variant/ankrd1-c-652-minus-2a-t), [ANKRD1 c.849+1G>C](/variant/ankrd1-c-849-plus-1g-c), [ANKRD1 p.Ala175Thr](/variant/ankrd1-p-ala175thr), [ANKRD1 p.Ala259Val](/variant/ankrd1-p-ala259val), [ANKRD1 p.Arg100Ser](/variant/ankrd1-p-arg100ser), [ANKRD1 p.Arg154Trp](/variant/ankrd1-p-arg154trp), [ANKRD1 p.Arg66Ter](/variant/ankrd1-p-arg66ter).

### 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 543938). 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.*