KLHL40

Chr 3

kelch like family member 40

Also known as: KBTBD5, NEM8, SRYP, SYRP

NCBI Gene: 131377 ENSG00000157119 UniProt: Q2TBA0

The protein contains BACK, BTB/POZ, and Kelch repeat domains and localizes to the cytoplasm, though its exact cellular function remains unknown. Mutations cause nemaline myopathy with autosomal recessive inheritance. The predicted gain-of-function mechanism suggests that pathogenic variants likely alter normal protein function rather than cause loss of function.

ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a protein containing a BACK domain, a BTB/POZ domain, and 5 Kelch repeats, however, its exact function is not known. The gene and the multi-domain protein structure are conserved across different taxa, including primates, rodents, chicken and zebrafish. [provided by RefSeq, Dec 2012]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.92

Clinical Summary— KLHL40

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Gene-Disease Validity (ClinGen)

nemaline myopathy 8 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

45 unique Pathogenic / Likely Pathogenic· 312 VUS of 594 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?

0.92LOEUF

pLI 0.000

Z-score 1.83

OE 0.57 (0.36–0.92)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.02Z-score

OE missense 1.00 (0.92–1.08)

420 obs / 421.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.57 (0.36–0.92)

0≤0.351.4

Missense OE?1.00 (0.92–1.08)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 12 / 21.0Missense obs/exp: 420 / 421.3Syn Z: 0.14

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveKLHL40-related nemaline myopathyLOFAR

This gene — mechanism propensity

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

0.75top 25%

GOF

0.75top 25%

LOF

0.2582th %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

594 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27

Likely Pathogenic18

VUS312

Likely Benign204

Benign21

Conflicting12

Pathogenic

Likely Pathogenic

312

VUS

204

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	23	4	0	0	27
Likely Pathogenic	14	4	0	0	18
VUS	3	298	7	4	312
Likely Benign	0	4	42	158	204
Benign	0	6	10	5	21
Conflicting	—				12
Total	40	316	59	167	594

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

View in ClinVar →

7 pathogenic / likely-pathogenic (of 10) ClinVar copy-number / structural variants overlap KLHL40 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →