RAPGEF4 p.Pro548=
c.1644G>A · rs35825006 · VCV774835
Benign
Multiple submitters
Classification
Benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
low-frequency (popmax 2.23%, afr)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 2.4 | GERP -1.6, phastCons 1 |
| Overall | ||
| CADD | 12.16 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
2.23%
African / African-American · 1,670/74,964 alleles
Filtering AF
2.14%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 2.1%
Overall
0.178%
2,880/1,613,864 alleles · low-frequency
exomes 1,834/1,461,716 · genomes 1,046/152,148 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 2.23% | 45 |
| South Asian | 0.405% | 247 |
| Middle Eastern | 0.33% | 303 |
| Remaining individualsnot grpmax-eligible | 0.203% | 492 |
| Admixed American | 0.173% | 577 |
| Ashkenazi Jewishnot grpmax-eligible | 0.111% | 897 |
| European (non-Finnish) | 0.0459% | 2,181 |
| Finnishnot grpmax-eligible | 0.0235% | 4,264 |
| East Asian | 0.00223% | 44,870 |
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- RAPGEF4
- Protein
- p.Pro548=
- Coding
- c.1644G>A
- MANE Select
- NM_007023
- dbSNP
- rs35825006
- Type
- single nucleotide variant
- Location
- chr2:173001330 (GRCh38)
- Gene constraint
- LOEUF 0.542 · pLI 0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 87.41
- Residue 548
- the n-terminal ras-gef domain
Similar variants
- RAPGEF4 p.Pro548Leu Uncertain significance ★ ⚠ same residue
- RAPGEF4 p.Gly706Arg Likely benign ★★ same type
- RAPGEF4 p.Ile516Val Benign ★★ same type
- RAPGEF4 p.Thr231= Benign ★★ same type
- RAPGEF4 p.Ala125Thr Uncertain significance ★ ⚠ same type
- RAPGEF4 p.Ala13Val Uncertain significance ★ ⚠ same type
- RAPGEF4 p.Ala17Ser Uncertain significance ★ ⚠ same type
- RAPGEF4 p.Ala213Thr Uncertain significance ★ ⚠ same type
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/rapgef4-p-pro548 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown