SRPX2

Chr X

sushi repeat containing protein X-linked 2

Also known as: BPP, CBPS, PMGX, RESDX, SRPUL

NCBI Gene: 27286 ENSG00000102359 UniProt: O60687 OMIM: 300642

The SRPX2 protein is secreted and contains sushi repeat motifs, functioning as a ligand for the urokinase plasminogen activator surface receptor and promoting synapse formation, angiogenesis, and cellular migration. Mutations cause X-linked rolandic epilepsy with impaired intellectual development and speech dyspraxia, typically affecting the perisylvian brain region critical for language and cognitive development. This gene shows low constraint against loss-of-function variants (LOEUF 0.538), consistent with X-linked inheritance where hemizygous males are primarily affected.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a secreted protein that contains three sushi repeat motifs. The encoded protein may play a role in the development of speech and language centers in the brain. This protein may also be involved in angiogenesis. Mutations in this gene are the cause of bilateral perisylvian polymicrogyria, rolandic epilepsy, speech dyspraxia and cognitive disability. [provided by RefSeq, May 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

?Rolandic epilepsy, impaired intellectual development, and speech dyspraxiaMIM #300643

Clinical highlights

Gene–disease validity (ClinGen)

Refuted · epilepsy · XL · ClinGen 2023

evidence has disproved this relationship

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.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.54

LOEUF

Mechanism· predicted

📖

GeneReview available — SRPX2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.54LOEUF

pLI 0.048

Z-score 3.27

OE 0.29 (0.16–0.54)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.23Z-score

OE missense 0.96 (0.85–1.07)

204 obs / 213.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.29 (0.16–0.54)

0≤0.351.4

Missense OE?0.96 (0.85–1.07)

0≤0.61.4

Synonymous OE?0.82

0≤1.21.6

LoF obs/exp: 7 / 24.4Missense obs/exp: 204 / 213.3Syn Z: 1.21

Background carrier burden — how many people carry a rare variant somewhere in SRPX2?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

396 rare PASS variants

Rare truncating (LoF)

1 in 6,400

41 rare PASS variants

Rare synonymous (reference)

1 in 430

131 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SRPX2. 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)	~561k	1 in 200	1 in 3,500
South Asian	~36k	1 in 88	1 in 2,400
Remaining (unassigned)	~31k	1 in 86	1 in 5,500
European (Finnish)	~27k	1 in 330	≈ 1 in 11,000
Admixed American	~23k	1 in 110	≈ 1 in 5,900
African / African American	~21k	1 in 90	≈ 1 in 8,800
East Asian	~20k	1 in 230	≈ 1 in 5,000
Ashkenazi Jewish	~13k	1 in 1,600	≈ 1 in 3,200
Middle Eastern	~2,758	1 in 130	≈ 1 in 2,800

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): 10 of 10 coding exons well covered in gnomAD exomes. Genomes: 9 of 10 (exon 10 below).? see exons ↓