TBCE

Chr 1AR

tubulin folding cofactor E

Also known as: HRD, KCS, KCS1, PEAMO, pac2

NCBI Gene: 6905ENSG00000284770UniProt: Q15813

Cofactor E is one of four proteins (cofactors A, D, E, and C) involved in the pathway leading to correctly folded beta-tubulin from folding intermediates. Cofactors A and D are believed to play a role in capturing and stabilizing beta-tubulin intermediates in a quasi-native confirmation. Cofactor E binds to the cofactor D/beta-tubulin complex; interaction with cofactor C then causes the release of beta-tubulin polypeptides that are committed to the native state. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Encephalopathy, progressive, with amyotrophy and optic atrophyMIM #617207
AR
Hypoparathyroidism-retardation-dysmorphism syndromeMIM #241410
AR
Kenny-Caffey syndrome, type 1MIM #244460
AR
581
ClinVar variants
84
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— TBCE
🧬
Gene-Disease Validity (ClinGen)
encephalopathy, progressive, with amyotrophy and optic atrophy · ARModerate

Moderate evidence — consider for supplementary testing

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
84 Pathogenic / Likely Pathogenic· 155 VUS of 581 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.81LOEUF
pLI 0.000
Z-score 2.44
OE 0.54 (0.37–0.81)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.12Z-score
OE missense 0.98 (0.89–1.08)
276 obs / 281.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.54 (0.37–0.81)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.98 (0.89–1.08)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.05
0≤1.21.6
LoF obs/exp: 18 / 33.2Missense obs/exp: 276 / 281.7Syn Z: -0.40

ClinVar Variant Classifications

581 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic66
Likely Pathogenic18
VUS155
Likely Benign275
Benign64
Conflicting3
66
Pathogenic
18
Likely Pathogenic
155
VUS
275
Likely Benign
64
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
23
0
43
0
66
Likely Pathogenic
11
0
7
0
18
VUS
8
119
23
5
155
Likely Benign
1
8
133
133
275
Benign
1
0
62
1
64
Conflicting
—3
Total44127268139581

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

View in ClinVar →

Protein Context — Lollipop Plot

TBCE · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

TBCE-related hypoparathyroidism-retardation-dysmorphism syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersSkeletal
G2P ↗

TBCE-related early-onset progressive encephalopathy with distal spinal muscular atrophy

strong
ARUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Encephalopathy, progressive, with amyotrophy and optic atrophy

MIM #617207

Molecular basis of disorder known

Autosomal recessive

Hypoparathyroidism-retardation-dysmorphism syndrome

MIM #241410

Molecular basis of disorder known

Autosomal recessive

Kenny-Caffey syndrome, type 1

MIM #244460

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — TBCE
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Expanding TBCE-related phenotype-novel variant causing rigid spine, eosinophilia, neutropenia, and nocturnal hypoxemia.
Badura-Stronka M et al.·J Appl Genet
2025Case report
Hypoparathyroidism-retardation-dysmorphism syndrome in a girl: A new variant not caused by a TBCE mutation--clinical report and review.
Courtens W et al.·Am J Med Genet A
2006Review
Expanding the Phenotypic Spectrum of Kenny-Caffey Syndrome.
Schigt H et al.·J Clin Endocrinol Metab
2023
Out-of-frame Translation Rescues a Loss-of-function Variant in a Novel TBCE Phenotype.
Sparber P et al.·J Clin Endocrinol Metab
2025Case report
[Kenny-Caffey syndrome and its related syndromes].
Isojima T et al.·Nihon Rinsho
2015Review
Broadening the spectrum phenotype of TBCE-related neuron neurodegeneration.
Battini R et al.·Brain Dev
2021Case report
Oligogenic analysis across broad phenotypes of 46,XY differences in sex development associated with NR5A1/SF-1 variants: findings from the international SF1next study.
Kouri C et al.·EBioMedicine
2025
The development of the parathyroid gland: from fish to human.
Zajac JD et al.·Curr Opin Nephrol Hypertens
2008Review
Mutation of TBCE causes hypoparathyroidism-retardation-dysmorphism and autosomal recessive Kenny-Caffey syndrome.
Parvari R et al.·Nat Genet
2002
Phenotypic variability in progressive encephalopathy with brain atrophy and thin corpus callosum: insights from two families.
Aynekin B et al.·Neurogenetics
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools