MAP2K2 p.Phe57Val
c.169T>G · rs121434498 · VCV8273
ClinGen expert panel — RASopathy VCEP
Pathogenic for cardiofaciocutaneous syndrome. Applied ACMG criteria (verbatim):
PM2 PS2_VeryStrong PM1 PP2 PP3
Curation rationale (ClinGen, verbatim)
The c.169T>G (p.Phe57Val) variant in MAP2K2 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 18042262). The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of MAP2K2 (PM1; PMID 29493581). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the MAP2K2 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Phe57Val variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PM1, PM2, PP2, PP3.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9911 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.941 | strongly pathogenic-leaning |
| SaProt | LLR -15.62 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 11 | GERP 1.6, phastCons 1 |
| Regional constraint | o/e 0.67 | unconstrained · MANE · 18 kb · p 1.4e-08 · regional, not allelic |
| Overall | ||
| CADD | 28.3 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- MAP2K2
- Protein
- p.Phe57Val
- Coding
- c.169T>G
- MANE Select
- NM_030662
- dbSNP
- rs121434498
- Type
- single nucleotide variant
- Location
- chr19:4117553 (GRCh38)
- Gene constraint
- LOEUF 0.858 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 82.54 · 3 PDB
- Residue 57
- a UniProt-annotated variant site (in cfc4)
Similar variants
- MAP2K2 p.Phe57Cys Pathogenic ★★★ same residue
- MAP2K2 p.Phe57Leu Pathogenic/Likely pathogenic ★★ same residue
- MAP2K2 p.Phe57Ile Uncertain significance ★ ⚠ same residue
- MAP2K2 p.Phe57Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
- MAP2K2 p.Phe57= Likely benign ★ same residue
- MAP2K2 p.Glu207Lys Likely pathogenic ★★★ same condition
- MAP2K2 p.Pro128Gln Pathogenic ★★★ same condition
- MAP2K2 p.Tyr134Cys Likely 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/map2k2-p-phe57val (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown