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…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.36

LOEUF

Multiple*

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in EPHA6?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 45

1,555 rare PASS variants

Rare truncating (LoF)

1 in 950

163 rare PASS variants

Rare synonymous (reference)

1 in 66

609 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for EPHA6. 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 61	1 in 1,100
South Asian	~43k	1 in 49	1 in 780
Remaining (unassigned)	~30k	1 in 33	1 in 780
European (Finnish)	~27k	1 in 120	1 in 1,400
Admixed American	~22k	1 in 39	1 in 680
African / African American	~21k	1 in 47	1 in 1,100
East Asian	~20k	1 in 43	1 in 1,900
Ashkenazi Jewish	~13k	1 in 170	≈ 1 in 6,300
Middle Eastern	~2,884	1 in 53	≈ 1 in 2,800

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): 14 of 18 coding exons well covered in gnomAD exomes; exons 2, 9, 13, 18 marginal. Genomes: all 18.? see exons ↓