FCHSD2

Chr 11

FCH and double SH3 domains 2

Also known as: NWK, NWK1, SH3MD3

NCBI Gene: 9873 ENSG00000137478 UniProt: O94868

This adapter protein regulates clathrin-mediated endocytosis by binding phosphatidylinositol phosphates at the plasma membrane and promoting actin polymerization through Arp2/3 complex activation. Mutations cause autosomal recessive developmental and epileptic encephalopathy with onset in infancy, characterized by severe intellectual disability, seizures, and brain abnormalities. The gene shows significant constraint against loss-of-function variants (LOEUF 0.366), indicating that complete loss of protein function is likely pathogenic.

ResearchSummary from RefSeq, UniProt

Enables phosphatidylinositol-3,4,5-trisphosphate binding activity and phosphatidylinositol-3,4-bisphosphate binding activity. Involved in clathrin-dependent endocytosis and positive regulation of Arp2/3 complex-mediated actin nucleation. Located in clathrin-coated pit and plasma membrane. [provided by Alliance of Genome Resources, Jul 2025]

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

0.37

LOEUF

—

Mechanism

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.37LOEUF

pLI 0.566

Z-score 4.95

OE 0.22 (0.13–0.37)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.84Z-score

OE missense 0.74 (0.67–0.81)

289 obs / 391.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.22 (0.13–0.37)

0≤0.351.4

Missense OE?0.74 (0.67–0.81)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 10 / 46.4Missense obs/exp: 289 / 391.7Syn Z: 0.42

Background carrier burden — how many people carry a rare variant somewhere in FCHSD2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 83

835 rare PASS variants

Rare truncating (LoF)

1 in 3,700

88 rare PASS variants

Rare synonymous (reference)

1 in 110

301 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FCHSD2. 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 96	1 in 4,300
South Asian	~43k	1 in 53	1 in 5,100
Remaining (unassigned)	~30k	1 in 84	1 in 2,300
European (Finnish)	~27k	1 in 480	1 in 2,400
Admixed American	~22k	1 in 77	≈ 1 in 4,500
African / African American	~21k	1 in 69	1 in 2,900
East Asian	~20k	1 in 74	≈ 1 in 6,400
Ashkenazi Jewish	~13k	1 in 490	≈ 1 in 3,600
Middle Eastern	~2,884	1 in 99	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): 15 of 20 coding exons well covered in gnomAD exomes; exon 7 poorly covered; exons 2, 3, 4, 12 marginal. Genomes: all 20.? see exons ↓