EPHA6

Chr 3

EPH receptor A6

Also known as: EHK-2, EHK2, EK12, EPA6, HEK12, PRO57066

NCBI Gene: 285220 ENSG00000080224 UniProt: Q9UF33 OMIM: 600066

EPHA6 encodes a receptor tyrosine kinase that binds ephrin-A ligands to mediate bidirectional cell signaling important for axon guidance and neural development. Mutations cause autosomal recessive spastic paraplegia and intellectual disability. The gene shows significant constraint against loss-of-function variants (LOEUF 0.357), indicating intolerance to disruption.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable transmembrane-ephrin receptor activity. Predicted to be involved in axon guidance and ephrin receptor signaling pathway. Predicted to be located in membrane. Predicted to be active in dendrite and plasma membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.36

Clinical Summary— EPHA6

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.67) — some intolerance to loss-of-function variants.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.36LOEUF

pLI 0.670

Z-score 5.05

OE 0.21 (0.13–0.36)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.50Z-score

OE missense 0.83 (0.77–0.89)

505 obs / 609.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.21 (0.13–0.36)

0≤0.351.4

Missense OE?0.83 (0.77–0.89)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 10 / 47.5Missense obs/exp: 505 / 609.4Syn Z: -1.11

This gene — mechanism propensity

0.6455th %ile

GOF

0.7127th %ile

LOF

0.4430th %ile

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

GOFprediction above median

DNprediction 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.