KHDRBS3

Chr 8

KH RNA binding domain containing, signal transduction associated 3

Also known as: Etle, SALP, SLM-2, SLM2, T-STAR, TSTAR, etoile

NCBI Gene: 10656 ENSG00000131773 OMIM: 610421

The KHDRBS3 protein binds RNA and regulates alternative mRNA splicing, particularly of neurexins which are critical for synaptic function and targeting. Mutations cause autosomal recessive intellectual disability with variable features including developmental delay and neurological abnormalities. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.493), and its regulation of neurexin splicing at glutamatergic synapses explains the neurodevelopmental phenotype.

OMIM ResearchSummary from RefSeq, UniProt

Enables RNA binding activity; identical protein binding activity; and protein domain specific binding activity. Predicted to be involved in regulation of alternative mRNA splicing, via spliceosome and spermatogenesis. Located in nucleoplasm. Part of protein-containing complex. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOEUF 0.49

Clinical Summary— KHDRBS3

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.22) despite low pLI — interpret in context.

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ClinVar Variants

41 VUS of 55 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.49LOEUF

pLI 0.442

Z-score 3.13

OE 0.22 (0.10–0.49)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.32Z-score

OE missense 0.73 (0.63–0.84)

136 obs / 186.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.22 (0.10–0.49)

0≤0.351.4

Missense OE?0.73 (0.63–0.84)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 4 / 18.6Missense obs/exp: 136 / 186.7Syn Z: 0.09

ClinVar Variant Classifications

55 submitted variants in ClinVar

ClinVar

Classification Summary

VUS41

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	41	41
Likely Benign	0	0
Benign	0	0
Total	41	41

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

View in ClinVar →

54 pathogenic / likely-pathogenic (of 62) ClinVar copy-number / structural variants overlap KHDRBS3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →