RAPH1

Chr 2

Ras association (RalGDS/AF-6) and pleckstrin homology domains 1

Also known as: ALS2CR18, ALS2CR9, LPD, PREL-2, PREL2, RMO1, RalGDS/AF-6

NCBI Gene: 65059ENSG00000173166UniProt: Q70E73

This gene encodes a protein that belongs to the Mig10/Rap1-interacting adaptor molecule/Lamellipodin family of adapter proteins, which function in cell migration. Members of this family contain pleckstrin-homology domains, Ras-association domains, and proline-rich C-termini. The protein encoded by this gene regulates actin dynamics through interaction with Ena/Vasodilator proteins as well as direct binding to filamentous actin to regulate actin network assembly. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016]

220
ClinVar variants
30
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— RAPH1
⚡
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
30 Pathogenic / Likely Pathogenic· 163 VUS of 220 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.
0.22LOEUF
pLI 1.000
Z-score 5.69
OE 0.11 (0.05–0.22)
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.
1.39Z-score
OE missense 0.85 (0.79–0.91)
583 obs / 685.1 exp
Tolerant

Mild missense constraint

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.0.11 (0.05–0.22)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.85 (0.79–0.91)
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.1.07
0≤1.21.6
LoF obs/exp: 5 / 47.2Missense obs/exp: 583 / 685.1Syn Z: -0.94

ClinVar Variant Classifications

220 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29
Likely Pathogenic1
VUS163
Likely Benign11
Benign1
29
Pathogenic
1
Likely Pathogenic
163
VUS
11
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
29
0
29
Likely Pathogenic
0
0
1
0
1
VUS
0
159
4
0
163
Likely Benign
0
7
0
4
11
Benign
0
0
0
1
1
Total0166345205

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

View in ClinVar →

Protein Context — Lollipop Plot

RAPH1 · 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
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clinicopathological and prognostic significance of Ras association and pleckstrin homology domains 1 (RAPH1) in breast cancer.
Kurozumi S et al.·Breast Cancer Res Treat
2018
Association between RAPH1 Gene Haplotypes and CHE2 Locus Phenotypes.
A De Andrade F et al.·Ann Hum Genet
2016
The C5 Variant of the Butyrylcholinesterase Tetramer Includes a Noncovalently Bound 60 kDa Lamellipodin Fragment.
Schopfer LM et al.·Molecules
2017
Blood transcriptomic biomarkers in adult primary care patients with major depressive disorder undergoing cognitive behavioral therapy.
Redei EE et al.·Transl Psychiatry
2014Cohort
Bayesian colocalization of GWAS and eQTL signals reveals cell type-specific genes and regulatory variants for susceptibility to subtypes of ischemic stroke.
Seo Y et al.·Comput Biol Chem
2024
Two MER2-negative individuals with the same novel CD151 mutation and evidence for clinical significance of anti-MER2.
Karamatic Crew V et al.·Transfusion
2008Case report
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