Is MAP2K2 p.Arg281= (c.843G>A) pathogenic?

MAP2K2 p.Arg281= (c.843G>A) is classified Likely benign in MAP2K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-10-20). Very rare (popmax 0.00017%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with MAP2K2 p.Arg281= (c.843G>A)?

MAP2K2 p.Arg281= (c.843G>A) is associated with Cardiovascular phenotype (ClinVar).

How common is MAP2K2 p.Arg281= (c.843G>A) in the general population?

MAP2K2 p.Arg281= (c.843G>A) is very rare (popmax 0.00017%, nfe) (gnomAD).

MAP2K2 p.Arg281=

c.843G>A · rs774671895 · VCV1763394

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

Cardiovascular phenotype

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 1.8	GERP -0.67, phastCons 1
Overall
CADD	7.216	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,176,694 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000187% 3/1,605,958 alleles · very rare exomes 3/1,453,598 · genomes 0/152,360 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00161%	62,262
European (non-Finnish)grpmax	0.00017%	588,346

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg281=
Coding: c.843G>A
MANE Select: NM_030662
dbSNP: rs774671895
Type: single nucleotide variant
Location: chr19:4099277 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 281: the protein kinase domain

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

Similar variants

MAP2K2 p.Arg281Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
MAP2K2 p.Arg281Gln Uncertain significance ★★★ ⚠ same residue
MAP2K2 p.Arg281Pro Uncertain significance ★ ⚠ same residue
MAP2K2 p.Gly132Asp Pathogenic/Likely pathogenic ★★ same condition
MAP2K2 c.450+5G>A Uncertain significance ★★ same condition
MAP2K2 p.Ala355Val Uncertain significance ★★ ⚠ same condition
MAP2K2 p.Ala358Val Uncertain significance ★★ ⚠ same condition
MAP2K2 p.Ala380Val 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-arg281 (accessed [today's date]).

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