SPRY2

Chr 13

sprouty RTK signaling antagonist 2

Also known as: IGAN3, hSPRY2

NCBI Gene: 10253 ENSG00000136158 UniProt: O43597

The protein antagonizes fibroblast growth factor (FGF) signaling pathways by inhibiting FGF-mediated ERK1/2 phosphorylation and also inhibits CBL-mediated EGFR ubiquitination. Mutations cause IgA nephropathy with autosomal dominant inheritance. This gene is highly constrained against loss-of-function variants (pLI = 0.97), suggesting additional phenotypes may be associated with pathogenic variants.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein belonging to the sprouty family. The encoded protein contains a carboxyl-terminal cysteine-rich domain essential for the inhibitory activity on receptor tyrosine kinase signaling proteins and is required for growth factor stimulated translocation of the protein to membrane ruffles. In primary dermal endothelial cells this gene is transiently upregulated in response to fibroblast growth factor two. This protein is indirectly involved in the non-cell autonomous inhibitory effect on fibroblast growth factor two signaling. The protein interacts with Cas-Br-M (murine) ectropic retroviral transforming sequence, and can function as a bimodal regulator of epidermal growth factor receptor/mitogen-activated protein kinase signaling. This protein may play a role in alveoli branching during lung development as shown by a similar mouse protein. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtIgA nephropathy 3

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

0.27

LOEUF· LoF intol.

LOF

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.27LOEUF

pLI 0.971

Z-score 3.07

OE 0.00 (0.00–0.27)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

0.97Z-score

OE missense 0.79 (0.69–0.91)

139 obs / 175.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.27)

0≤0.351.4

Missense OE?0.79 (0.69–0.91)

0≤0.61.4

Synonymous OE?1.21

0≤1.21.6

LoF obs/exp: 0 / 11.0Missense obs/exp: 139 / 175.3Syn Z: -1.37

Background carrier burden — how many people carry a rare variant somewhere in SPRY2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 270

365 rare PASS variants

Rare truncating (LoF)

1 in 11,000

33 rare PASS variants

Rare synonymous (reference)

1 in 390

188 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SPRY2. 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 290	1 in 13,000
South Asian	~43k	1 in 190	≈ 1 in 43,000
Remaining (unassigned)	~30k	1 in 230	none seen
European (Finnish)	~27k	1 in 360	none seen
Admixed American	~22k	1 in 190	none seen
African / African American	~21k	1 in 190	≈ 1 in 4,900
East Asian	~20k	1 in 290	≈ 1 in 20,000
Ashkenazi Jewish	~13k	1 in 1,400	none seen
Middle Eastern	~2,884	1 in 210	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 1 coding exons well covered in gnomAD exomes and genomes.? see exons ↓