SEMA4C

Chr 2

semaphorin 4C

Also known as: M-SEMA-F, SEMACL1, SEMAF, SEMAI

NCBI Gene: 54910 ENSG00000168758 UniProt: Q9C0C4 OMIM: 604462

The SEMA4C protein is a cell surface receptor that regulates brain development, axon guidance, and cell migration through downstream signaling pathways including RHOA activation and stress-activated MAPK cascade. Mutations cause autosomal dominant developmental delays, intellectual disability, and behavioral abnormalities with childhood onset. This gene is highly constrained against loss-of-function variants (pLI = 1.0, LOEUF = 0.12), indicating intolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable chemorepellent activity; neuropilin binding activity; and semaphorin receptor binding activity. Involved in muscle cell differentiation and positive regulation of stress-activated MAPK cascade. Located in obsolete extracellular space. [provided by Alliance of Genome Resources, Jun 2026]

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

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P/LP missense

0.12

LOEUF· LoF intol.

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Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.12LOEUF

pLI 1.000

Z-score 5.63

OE 0.03 (0.01–0.12)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

2.39Z-score

OE missense 0.71 (0.65–0.77)

379 obs / 534.1 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.03 (0.01–0.12)

0≤0.351.4

Missense OE?0.71 (0.65–0.77)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 1 / 38.9Missense obs/exp: 379 / 534.1Syn Z: 0.62

Background carrier burden — how many people carry a rare variant somewhere in SEMA4C?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 62

866 rare PASS variants

Rare truncating (LoF)

1 in 3,900

64 rare PASS variants

Rare synonymous (reference)

1 in 110

469 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SEMA4C. 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 69	1 in 3,700
South Asian	~43k	1 in 44	1 in 2,500
Remaining (unassigned)	~30k	1 in 64	≈ 1 in 7,500
European (Finnish)	~27k	1 in 150	1 in 5,200
Admixed American	~22k	1 in 61	≈ 1 in 11,000
African / African American	~21k	1 in 59	1 in 1,800
East Asian	~20k	1 in 87	≈ 1 in 20,000
Ashkenazi Jewish	~13k	1 in 140	≈ 1 in 4,400
Middle Eastern	~2,884	1 in 57	none seen

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 14 coding exons well covered in gnomAD exomes and genomes.? see exons ↓