SRGAP1

Chr 12ADSomatic

SLIT-ROBO Rho GTPase activating protein 1

Also known as: ARHGAP13, NMTC2

NCBI Gene: 57522ENSG00000196935UniProt: Q7Z6B7

The protein encoded by this gene is a GTPase activator, working with the GTPase CDC42 to negatively regulate neuronal migration. The encoded protein interacts with the transmembrane receptor ROBO1 to inactivate CDC42. [provided by RefSeq, Sep 2016]

Primary Disease Associations & Inheritance

{Thyroid cancer, nonmedullary, 2}MIM #188470
ADSomatic
166
ClinVar variants
8
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— SRGAP1
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
8 Pathogenic / Likely Pathogenic· 121 VUS of 166 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.27LOEUF
pLI 0.998
Z-score 5.81
OE 0.15 (0.09–0.27)
Highly constrained

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

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.21Z-score
OE missense 0.75 (0.69–0.81)
454 obs / 607.0 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.15 (0.09–0.27)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.75 (0.69–0.81)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.88
0≤1.21.6
LoF obs/exp: 8 / 54.1Missense obs/exp: 454 / 607.0Syn Z: 1.39

ClinVar Variant Classifications

166 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8
VUS121
Likely Benign25
Benign12
8
Pathogenic
121
VUS
25
Likely Benign
12
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
7
0
8
Likely Pathogenic
0
0
0
0
0
VUS
2
116
3
0
121
Likely Benign
0
1
7
17
25
Benign
0
2
3
7
12
Total21202024166

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

View in ClinVar →

Protein Context — Lollipop Plot

SRGAP1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Thyroid cancer, nonmedullary, 2}

MIM #188470

Molecular basis of disorder known

Autosomal dominantSomatic mutation
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
A neuronal Slit1-dependent program rescues oligodendrocyte differentiation and myelination under chronic hypoxic conditions.
Dai W et al.·Cell Rep
2025
SRGAP1 Controls Small Rho GTPases To Regulate Podocyte Foot Process Maintenance.
Rogg M et al.·J Am Soc Nephrol
2021
srGAP1 mediates the migration inhibition effect of Slit2-Robo1 in colorectal cancer.
Feng Y et al.·J Exp Clin Cancer Res
2016
Mutations of the SLIT2-ROBO2 pathway genes SLIT2 and SRGAP1 confer risk for congenital anomalies of the kidney and urinary tract.
Hwang DY et al.·Hum Genet
2015Clinical trial
MicroRNA-145 Promotes the Phenotype of Human Glioblastoma Cells Selected for Invasion.
Koo S et al.·Anticancer Res
2015
Familial non-medullary thyroid cancer: unraveling the genetic maze.
Peiling Yang S et al.·Endocr Relat Cancer
2016Review
SRGAP1 is a candidate gene for papillary thyroid carcinoma susceptibility.
He H et al.·J Clin Endocrinol Metab
2013
Familial nonmedullary thyroid cancer: a case series in Iranian patients with a meta-review of case series.
Mohammadi Zaniani Z et al.·Lab Med
2024Review
[A Familial Non Medullary Thyroid Carcinoma (FNMTC) : a clinical and genetic update].
Valdes-Socin H et al.·Rev Med Liege
2016Review
Familial non-medullary thyroid carcinoma: clinico-pathological features, current knowledge and novelty regarding genetic risk factors.
Cirello V·Minerva Endocrinol (Torino)
2021Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools