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: 65059 ENSG00000173166 UniProt: Q70E73 OMIM: 609035

The protein regulates actin dynamics and lamellipodial formation through interaction with Ena/VASP proteins and direct binding to filamentous actin, mediating localized membrane signals and cell adhesion. Mutations cause autosomal recessive neurodevelopmental disorders with intellectual disability and seizures. This gene is highly constrained against loss-of-function variants, indicating that complete loss of protein function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.22

Clinical Summary— RAPH1

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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.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 161 VUS of 189 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

1.39Z-score

OE missense 0.85 (0.79–0.91)

583 obs / 685.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.11 (0.05–0.22)

0≤0.351.4

Missense OE?0.85 (0.79–0.91)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 5 / 47.2Missense obs/exp: 583 / 685.1Syn Z: -0.94

This gene — mechanism propensity

0.4289th %ile

GOF

0.3689th %ile

LOF

0.76top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.22

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

189 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS161

Likely Benign11

Benign1

Pathogenic

161

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	1	0	1
Likely Pathogenic	0	0	0	0	0
VUS	1	160	0	0	161
Likely Benign	0	7	0	4	11
Benign	0	0	0	1	1
Total	1	167	1	5	174

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

View in ClinVar →

29 pathogenic / likely-pathogenic (of 32) ClinVar copy-number / structural variants overlap RAPH1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →