# NM_017946.4(FKBP14):c.615A>G (p.Thr205=)

https://sugi.bio/variant/fkbp14-p-thr205

## Summary

**FKBP14 p.Thr205= (c.615A>G)** is classified **Likely benign** in FKBP14 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). Ultra-rare (popmax 0.0139%, amr); Associated with Ehlers-Danlos syndrome, kyphoscoliotic type, 2.

**At a glance:** Likely benign · review: Single submitter · rsID rs577454244 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0139%, amr)

## For patients & families {#patients}

This is a change in the FKBP14 gene that is classified as likely benign — not considered 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 |
| Diagnostic panels | FKBP14 is a diagnostic-grade gene on 8 Genomics England panels |

**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.Thr205= |
| Coding change (HGVS c.) | c.615A>G |
| MANE Select transcript | [NM_017946](https://www.ncbi.nlm.nih.gov/nuccore/NM_017946) |
| dbSNP | [rs577454244](https://www.ncbi.nlm.nih.gov/snp/rs577454244/) |
| Variant type | single nucleotide variant |
| Location | chr7:30014756-30014756 (GRCh38) |
| ClinVar | [VCV2428030](https://www.ncbi.nlm.nih.gov/clinvar/variation/2428030/) |

**All HGVS expressions:** `LRG_454:g.17046A>G`, `LRG_454t1:c.615A>G`, `NC_000007.13:g.30054372T>C`, `NC_000007.14:g.30014756T>C`, `NG_032173.1:g.17046A>G`, `NM_017946.4:c.615A>G`, `NR_046478.2:n.901A>G`, `NR_046479.2:n.657A>G`

## 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 -0.406, GERP 1.85, phastCons 0.289 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 9.177**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for FKBP14 (251 scored positions, the nearest 2 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.0139%** (amr) · FAF95 0.00687% · FAF99 0.00501% · 8/57,452 in the highest group · 9/1,603,842 alleles overall — ultra-rare (popmax 0.0139%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0139% | 7,181 |
| European (non-Finnish) | 8.5e-05% | 1,176,466 |

*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}

**FKBP14** population constraint: LOEUF 1.342, pLI 4.1885e-06, missense-Z 0.32492; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **205** lies in an α-helix; the ef-hand 2 domain.

AlphaFold model confidence (whole protein): pLDDT 88.27, 67% of residues very-high.

**2 experimental structure(s)** (PDB): [4DIP](https://www.rcsb.org/structure/4DIP), [4MSP](https://www.rcsb.org/structure/4MSP).

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

*Describes the biological roles of FKBP14 (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.*


### Pathways affected {#pathways}

FKBP14 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [XBP1(S) activates chaperone genes](https://reactome.org/content/detail/R-HSA-381038) | other |

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-16.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-16 |

## 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, Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss, Ehlers-Danlos syndrome, kyphoscoliotic and deafness type, FKBP14-Kyphoscoliotic Ehlers-Danlos Syndrome.

## Similar variants {#similar}

Related FKBP14 variant pages (same residue, condition, or type): [FKBP14 p.Ser143Ter](/variant/fkbp14-p-ser143ter), [FKBP14 c.198-3T>C](/variant/fkbp14-c-198-minus-3t-c), [FKBP14 p.Arg135Gln](/variant/fkbp14-p-arg135gln), [FKBP14 p.Arg2Ser](/variant/fkbp14-p-arg2ser), [FKBP14 p.Asp181Glu](/variant/fkbp14-p-asp181glu), [FKBP14 p.Asp46Gly](/variant/fkbp14-p-asp46gly), [FKBP14 p.Asp46Tyr](/variant/fkbp14-p-asp46tyr), [FKBP14 p.Glu99Gln](/variant/fkbp14-p-glu99gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2428030). 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.*