FKBP6

Chr 7

FKBP prolyl isomerase family member 6 (inactive)

Also known as: FKBP36, SPGF77

NCBI Gene: 8468 ENSG00000077800 UniProt: O75344

FKBP6 encodes a peptidyl-prolyl isomerase that functions as a co-chaperone with HSP90 and has an essential role in spermatogenesis by repressing transposable elements through the piRNA pathway. Mutations cause autosomal recessive spermatogenic failure, resulting in male infertility. The gene shows minimal constraint against loss-of-function variants in the general population.

ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a cis-trans peptidyl-prolyl isomerase that may function in immunoregulation and basic cellular processes involving protein folding and trafficking. This gene is located in a chromosomal region that is deleted in Williams-Beuren syndrome. Defects in this gene may cause male infertility. There are multiple pseudogenes for this gene located nearby on chromosome 7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.03

Clinical Summary— FKBP6

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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

5 unique Pathogenic / Likely Pathogenic· 38 VUS of 50 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.03LOEUF

pLI 0.000

Z-score 1.46

OE 0.64 (0.41–1.03)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.67Z-score

OE missense 0.86 (0.75–0.98)

154 obs / 179.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.64 (0.41–1.03)

0≤0.351.4

Missense OE?0.86 (0.75–0.98)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 12 / 18.9Missense obs/exp: 154 / 179.1Syn Z: 0.77

This gene — mechanism propensity

0.76top 25%

GOF

0.76top 25%

LOF

0.1994th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

ClinVar Variant Classifications

50 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic3

VUS38

Likely Benign5

Benign2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	0	0	0	2
Likely Pathogenic	3	0	0	0	3
VUS	0	38	0	0	38
Likely Benign	0	3	1	1	5
Benign	0	1	1	0	2
Total	5	42	2	1	50

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

View in ClinVar →

162 pathogenic / likely-pathogenic (of 172) ClinVar copy-number / structural variants overlap FKBP6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →