MAP2K1 p.Ala283Val
c.848C>T · rs144080051 · VCV40756
ClinGen expert panel — RASopathy VCEP
Benign for RASopathy. Applied ACMG criteria (verbatim):
BP5 BA1
Curation rationale (ClinGen, verbatim)
The filtering allele frequency of the c.848C>T (p.Ala283Val) variant in the MAP2K1 gene is 0.052% for African chromosomes by the Exome Aggregation Consortium (10/10366 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; Partners LMM, GeneDx internal data; GTR ID: 21766, 26957; ClinVar SCV000207935.12; SCV000061262.5). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BA1, BP5.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.0646 | likely benign |
|---|---|---|
| REVEL | 0.019 | moderately benign-leaning |
| SaProt | LLR -6.71 | tolerated |
| ⇒ AlphaMissense, REVEL and SaProt all call this tolerated. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 1.4 | GERP 1.1, phastCons 0.79 |
| Regional constraint | o/e 0.61 | unconstrained · MANE · 5,593 bp · p 6.7e-08 · regional, not allelic |
| Overall | ||
| CADD | 21.5 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.0828% | 1,208 |
| Ashkenazi Jewishnot grpmax-eligible | 0.00338% | 29,604 |
| Remaining individualsnot grpmax-eligible | 0.0032% | 31,234 |
| Admixed American | 0.00167% | 60,004 |
| South Asian | 0.0011% | 91,080 |
| European (non-Finnish) | 0.000169% | 590,012 |
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
- MAP2K1
- Protein
- p.Ala283Val
- Coding
- c.848C>T
- MANE Select
- NM_002755
- dbSNP
- rs144080051
- Type
- single nucleotide variant
- Location
- chr15:66485144 (GRCh38)
- Gene constraint
- LOEUF 0.515 · pLI 0.97 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 84.05 · 99 PDB
- Residue 283
- the protein kinase domain; the 'raf1-binding' region
Similar variants
- MAP2K1 p.Ala283= Likely benign ★★ same residue
- MAP2K1 p.Arg108Leu Likely pathogenic ★★★ same condition
- MAP2K1 p.Asn122Asp Pathogenic ★★★ ⚠ same condition
- MAP2K1 p.Asp67Asn Pathogenic ★★★ same condition
- MAP2K1 p.Glu203Gly Pathogenic ★★★ same condition
- MAP2K1 p.Leu42Arg Likely pathogenic ★★★ same condition
- MAP2K1 p.Leu42Phe Pathogenic ★★★ same condition
- MAP2K1 p.Leu92Arg Pathogenic ★★★ same condition
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/map2k1-p-ala283val (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown