# NM_017946.4(FKBP14):c.518C>T (p.Ala173Val)

https://sugi.bio/variant/fkbp14-p-ala173val

## Summary

**FKBP14 p.Ala173Val (c.518C>T)** is classified **Conflicting classifications of pathogenicity** in FKBP14 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-10-24). AlphaMissense: likely benign (0.1256); Very rare (popmax 0.00406%, afr); Associated with Cardiovascular phenotype.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs757164371 · 3 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00406%, afr)

## For patients & families {#patients}

This is a change in the FKBP14 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to Cardiovascular phenotype.

*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 | [FKBP14](https://sugi.bio/atlas/gene/FKBP14/) |
| Protein change (HGVS p.) | p.Ala173Val |
| Coding change (HGVS c.) | c.518C>T |
| MANE Select transcript | [NM_017946](https://www.ncbi.nlm.nih.gov/nuccore/NM_017946) |
| dbSNP | [rs757164371](https://www.ncbi.nlm.nih.gov/snp/rs757164371/) |
| Variant type | single nucleotide variant |
| Location | chr7:30014853-30014853 (GRCh38) |
| ClinVar | [VCV1036143](https://www.ncbi.nlm.nih.gov/clinvar/variation/1036143/) |

**All HGVS expressions:** `LRG_454:g.16949C>T`, `NC_000007.13:g.30054469G>A`, `NC_000007.14:g.30014853G>A`, `NG_032173.1:g.16949C>T`, `NM_017946.2:c.518C>T`, `NM_017946.4:c.518C>T`, `NR_046478.2:n.804C>T`, `NR_046479.2:n.560C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1256)
- REVEL 0.091 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -4.679 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 11.724, GERP 1.85, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.5**. 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 1.02** across the covering region of the MANE Select transcript (30,014,738–30,026,508), spanning 11,770 bp. Chi-square p 0.8. 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, Δ0.28 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 **0.00406%** (afr) · FAF95 0.003% · FAF99 0.00268% · 3/73,982 in the highest group · 52/1,599,336 alleles overall — very rare (popmax 0.00406%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00406% | 24,661 |
| European (non-Finnish) | 0.00391% | 25,567 |
| Remaining individuals (not grpmax-eligible) | 0.00323% | 30,943 |
| South Asian | 0.00114% | 87,678 |

*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}


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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-10-24.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Likely benign).

**Submission history:** 3 submissions (2021–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-01-17 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-24 |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-12-01 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, Ehlers-Danlos syndrome, kyphoscoliotic type, 2, not provided, Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss, Ehlers-Danlos syndrome, kyphoscoliotic and deafness type, FKBP14-Kyphoscoliotic Ehlers-Danlos Syndrome, none provided.

## 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 2026-10-14); 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 1036143). 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.*