TBCE

Chr 1AR

tubulin folding cofactor E

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

NCBI Gene: 6905 ENSG00000284770 UniProt: Q15813 OMIM: 604934

Cofactor E binds to the cofactor D/beta-tubulin complex and facilitates the release of correctly folded beta-tubulin committed to the native state, functioning as part of the tubulin folding pathway. Biallelic mutations cause autosomal recessive conditions including progressive encephalopathy with amyotrophy and optic atrophy, hypoparathyroidism-retardation-dysmorphism syndrome, and Kenny-Caffey syndrome type 1. The pathogenic mechanism appears to be dominant negative, disrupting proper microtubule formation essential for cellular structure and function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Encephalopathy, progressive, with amyotrophy and optic atrophyMIM #617207

Hypoparathyroidism-retardation-dysmorphism syndromeMIM #241410

Kenny-Caffey syndrome, type 1MIM #244460

Myopathy with rigid spine, scoliosis, and male-limited hypogonadotropic hypogonadismMIM #621734

Clinical highlights

Gene–disease validity (ClinGen)

Moderate · encephalopathy, progressive, with amyotrophy and optic atrophy · AR · ClinGen 2025

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.81

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — TBCE

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?

0.81LOEUF

pLI 0.000

Z-score 2.44

OE 0.54 (0.37–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.12Z-score

OE missense 0.98 (0.89–1.08)

276 obs / 281.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.54 (0.37–0.81)

0≤0.351.4

Missense OE?0.98 (0.89–1.08)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 18 / 33.2Missense obs/exp: 276 / 281.7Syn Z: -0.40

Background carrier burden — how many people carry a rare variant somewhere in TBCE?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 61

801 rare PASS variants

Rare truncating (LoF)

1 in 540

185 rare PASS variants

Rare synonymous (reference)

1 in 130

296 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TBCE. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 89	1 in 680
South Asian	~43k	1 in 68	1 in 780
Remaining (unassigned)	~30k	1 in 55	1 in 320
European (Finnish)	~27k	1 in 180	1 in 2,700
Admixed American	~22k	1 in 73	1 in 480
African / African American	~21k	1 in 77	1 in 830
East Asian	~20k	1 in 62	1 in 440
Ashkenazi Jewish	~13k	1 in 280	≈ 1 in 3,300
Middle Eastern	~2,884	1 in 67	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 16 coding exons well covered in gnomAD exomes and genomes.? see exons ↓