Is MAP2K2 p.Val86= (c.258C>A) pathogenic?

MAP2K2 p.Val86= (c.258C>A) is classified Benign/Likely benign in MAP2K2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-11-18). Ultra-rare (popmax 0.0529%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with MAP2K2 p.Val86= (c.258C>A)?

MAP2K2 p.Val86= (c.258C>A) is associated with Cardiovascular phenotype, cardiofaciocutaneous syndrome 4, RASopathy (ClinVar).

How common is MAP2K2 p.Val86= (c.258C>A) in the general population?

MAP2K2 p.Val86= (c.258C>A) is ultra-rare (popmax 0.0529%, nfe) (gnomAD).

MAP2K2 p.Val86=

c.258C>A · rs148437150 · VCV46230

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0529%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP -2.4, phastCons 1
Overall
CADD	11.53	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0529% European (non-Finnish) · 624/1,180,046 alleles

Filtering AF 0.0494% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0481%

Overall 0.0397% 641/1,613,874 alleles · ultra-rare exomes 609/1,461,676 · genomes 32/152,198 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0529%	1,891
African / African-American	0.016%	6,244
Remaining individualsnot grpmax-eligible	0.008%	12,496

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: MAP2K2
Protein: p.Val86=
Coding: c.258C>A
MANE Select: NM_030662
dbSNP: rs148437150
Type: single nucleotide variant
Location: chr19:4117464 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 86: the protein kinase domain; a β-strand; a binding site

Full MAP2K2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiofaciocutaneous syndrome 4 RASopathy

Similar variants

MAP2K2 p.Val86Ile Uncertain significance ★ ⚠ same residue
MAP2K2 p.Glu207Lys Likely pathogenic ★★★ same condition
MAP2K2 p.Phe57Cys Pathogenic ★★★ same condition
MAP2K2 p.Phe57Val Pathogenic ★★★ same condition
MAP2K2 p.Pro128Gln Pathogenic ★★★ same condition
MAP2K2 p.Tyr134Cys Likely pathogenic ★★★ same condition
MAP2K2 p.Tyr134His Pathogenic ★★★ same condition
MAP2K2 p.Arg231His Uncertain significance ★★★ ⚠ 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-val86 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown