FSD2

Chr 15

fibronectin type III and SPRY domain containing 2

This gene encodes a protein belonging to the FN3/SPRY family, though its specific cellular function remains unclear. Mutations cause autosomal recessive intellectual disability with seizures and spasticity. The gene shows minimal constraint against loss-of-function variants, consistent with recessive inheritance where heterozygous carriers are typically unaffected.

ResearchSummary from RefSeq

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.27

LOEUF

GOF

Mechanism· predicted

Some data sources returned errors (2)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.27LOEUF

pLI 0.000

Z-score 0.28

OE 0.95 (0.72–1.27)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.25Z-score

OE missense 0.96 (0.89–1.05)

377 obs / 391.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.95 (0.72–1.27)

0≤0.351.4

Missense OE?0.96 (0.89–1.05)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 33 / 34.8Missense obs/exp: 377 / 391.0Syn Z: -0.71

Background carrier burden — how many people carry a rare variant somewhere in FSD2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 56

985 rare PASS variants

Rare truncating (LoF)

1 in 640

167 rare PASS variants

Rare synonymous (reference)

1 in 120

381 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FSD2. 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 72	1 in 820
South Asian	~43k	1 in 52	1 in 300
Remaining (unassigned)	~30k	1 in 46	1 in 370
European (Finnish)	~27k	1 in 200	1 in 3,800
Admixed American	~22k	1 in 46	1 in 370
African / African American	~21k	1 in 64	1 in 1,000
East Asian	~20k	1 in 75	1 in 420
Ashkenazi Jewish	~13k	1 in 280	1 in 840
Middle Eastern	~2,884	1 in 64	≈ 1 in 720

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): 11 of 12 coding exons well covered in gnomAD exomes; exon 5 marginal. Genomes: all 12.? see exons ↓