FKBP14

Chr 7AR

FKBP prolyl isomerase 14

Also known as: EDSKMH, EDSKSCL2, FKBP22, IPBP12

NCBI Gene: 55033 ENSG00000106080 UniProt: Q9NWM8 OMIM: 614505

The protein is a peptidyl-prolyl isomerase located in the endoplasmic reticulum that accelerates protein folding, with particular preference for substrates containing 4-hydroxyproline modifications including type III collagen. Biallelic mutations cause Ehlers-Danlos syndrome, kyphoscoliotic type 2, which is inherited in an autosomal recessive pattern. The gene shows tolerance to loss-of-function variants in the general population (high LOEUF score), consistent with the recessive inheritance pattern where heterozygous carriers are typically unaffected.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a member of the FK506-binding protein family of peptidyl-prolyl cis-trans isomerases. The encoded protein is found in the lumen of the endoplasmic reticulum, where it is thought to accelerate protein folding. Defects in this gene are a cause of a type of Ehlers-Danlos syndrome (EDS). Both a protein-coding variant and noncoding variants are transcribed from this gene. [provided by RefSeq, Mar 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.661 OMIM phenotype

Clinical Summary— FKBP14

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

21 unique Pathogenic / Likely Pathogenic· 138 VUS of 290 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — FKBP14

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.66LOEUF

pLI 0.000

Z-score 0.07

OE 0.98 (0.58–1.66)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.09Z-score

OE missense 0.97 (0.83–1.15)

105 obs / 107.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.98 (0.58–1.66)

0≤0.351.4

Missense OE?0.97 (0.83–1.15)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 9 / 9.2Missense obs/exp: 105 / 107.7Syn Z: 0.78

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveFKBP14-related Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing lossLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6551th %ile

GOF

0.6346th %ile

LOF

0.3355th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

290 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11

Likely Pathogenic10

VUS138

Likely Benign109

Benign9

Conflicting7

Pathogenic

Likely Pathogenic

138

VUS

109

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	10	1	0	0	11
Likely Pathogenic	10	0	0	0	10
VUS	4	129	5	0	138
Likely Benign	0	6	38	65	109
Benign	0	0	8	1	9
Conflicting	—				7
Total	24	136	51	66	284

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

23 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap FKBP14 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →