Is MAP2K2 p.Ser226= (c.678C>T) pathogenic?

MAP2K2 p.Ser226= (c.678C>T) is classified Conflicting classifications of pathogenicity in MAP2K2 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-01-26). Ultra-rare (popmax 0.0527%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with MAP2K2 p.Ser226= (c.678C>T)?

MAP2K2 p.Ser226= (c.678C>T) is associated with Cardiovascular phenotype, RASopathy (ClinVar).

How common is MAP2K2 p.Ser226= (c.678C>T) in the general population?

MAP2K2 p.Ser226= (c.678C>T) is ultra-rare (popmax 0.0527%, nfe) (gnomAD).

MAP2K2 p.Ser226=

c.678C>T · rs200874968 · VCV46240

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0527%, 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 1.5	GERP -0.62, phastCons 1
Overall
CADD	12.38	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0527% European (non-Finnish) · 612/1,161,244 alleles

Filtering AF 0.0492% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0478%

Overall 0.0411% 647/1,575,772 alleles · ultra-rare exomes 606/1,423,504 · genomes 41/152,268 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0527%	1,897
Remaining individualsnot grpmax-eligible	0.0311%	3,215
Admixed American	0.0185%	5,405
African / African-American	0.00541%	18,487
Finnishnot grpmax-eligible	0.00325%	30,745

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.Ser226=
Coding: c.678C>T
MANE Select: NM_030662
dbSNP: rs200874968
Type: single nucleotide variant
Location: chr19:4101046 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 226: the protein kinase domain; a modified residue ((microbial infection) o-acetylserine; by yersinia yopj; alternate); a modified residue (phosphoserine; alternate)

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: RASopathy

Similar variants

MAP2K2 p.Glu207Lys Likely pathogenic ★★★ same condition
MAP2K2 p.Phe57Cys 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
MAP2K2 p.Arg231Leu Uncertain significance ★★★ ⚠ same condition
MAP2K2 p.Arg281Gln 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-ser226 (accessed [today's date]).

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