FSD2

Chr 15

fibronectin type III and SPRY domain containing 2

Also known as: SPRYD1

NCBI Gene: 123722 ENSG00000186628 UniProt: A1L4K1

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

This gene encodes a protein that belongs to the FN3/SPRY family of proteins. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ResearchGenerating clinical summary…

GOFmechanismLOEUF 1.27

Clinical Summary— FSD2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

94 VUS of 104 total submissions

Explore recent and relevant literature in Research Assistant →

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

This gene — mechanism propensity

0.6162th %ile

GOF

0.6442th %ile

LOF

0.4234th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction 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.

ClinVar Variant Classifications

104 submitted variants in ClinVar

ClinVar

Classification Summary

VUS94

Likely Benign5

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	94	94
Likely Benign	5	5
Benign	0	0
Total	99	99

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

33 pathogenic / likely-pathogenic (of 42) ClinVar copy-number / structural variants overlap FSD2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →