# NM_017946.4(FKBP14):c.523dup (p.Val175fs)

https://sugi.bio/variant/fkbp14-p-val175fs

## Summary

**FKBP14 p.Val175fs (c.523dup)** is classified **Likely pathogenic** in FKBP14 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-17). Associated with Ehlers-Danlos syndrome, kyphoscoliotic type, 2.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

> **Built without this gene's context.** ClinVar files this variant under an overlapping gene, so its own gene's record set does not contain it and this page is assembled from the variant alone. Gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up — absent from this page, not from the data.

## For patients & families {#patients}

This is a change in the FKBP14 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to Ehlers-Danlos syndrome, kyphoscoliotic type, 2.

*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.*

|  |  |
| --- | --- |
| Age of onset (of this condition) | Antenatal, Neonatal |

**Commonly reported features of Kyphoscoliotic Ehlers-Danlos syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypotonia — Very frequent (99-80%)
- Joint hypermobility — Very frequent (99-80%)
- Kyphoscoliosis — Very frequent (99-80%)
- Epicanthus — Frequent (79-30%)
- Low-set ears — Frequent (79-30%)
- Downslanted palpebral fissures — Frequent (79-30%)
- Synophrys — Frequent (79-30%)
- Hyperextensible skin — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017361/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [FKBP14](https://sugi.bio/atlas/gene/FKBP14/) |
| Protein change (HGVS p.) | p.Val175fs |
| Coding change (HGVS c.) | c.523dup |
| MANE Select transcript | [NM_017946](https://www.ncbi.nlm.nih.gov/nuccore/NM_017946) |
| Variant type | Duplication |
| Location | chr7:30014847-30014848 (GRCh38) |
| ClinVar | [VCV3775211](https://www.ncbi.nlm.nih.gov/clinvar/variation/3775211/) |

**All HGVS expressions:** `LRG_454:g.16954dup`, `LRG_454t1:c.522dup`, `NC_000007.13:g.30054465dup`, `NC_000007.14:g.30014849dup`, `NG_032173.1:g.16954dup`, `NM_017946.4:c.523dup`, `NR_046478.2:n.809dup`, `NR_046479.2:n.565dup`

## 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 11.114, GERP 1.85, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. For a truncating variant the loss-of-function impact is position-dependent — C-terminal / last-exon truncations may escape nonsense-mediated decay. *Descriptive; not an applied PVS1 code.*
- SpliceAI: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.

*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.*

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-11-17.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| 3billion | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-11-17 |

## Associated conditions {#conditions}

[Ehlers-Danlos syndrome, kyphoscoliotic type, 2](https://sugi.bio/atlas/disease/ehlers-danlos-syndrome-kyphoscoliotic-type-2/).

**Reported phenotype names (ClinVar):** Ehlers-Danlos syndrome, kyphoscoliotic type, 2, FKBP14-Kyphoscoliotic Ehlers-Danlos Syndrome, Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss, Ehlers-Danlos syndrome, kyphoscoliotic and deafness type.

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 3775211). 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.*