Is MAP2K2 p.Phe213= (c.639C>T) pathogenic?

MAP2K2 p.Phe213= (c.639C>T) is classified Likely benign in MAP2K2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-09-08). Very rare (popmax 0.00902%, sas); Associated with Cardiovascular phenotype.

What condition is associated with MAP2K2 p.Phe213= (c.639C>T)?

MAP2K2 p.Phe213= (c.639C>T) is associated with Cardiovascular phenotype, RASopathy (ClinVar).

How common is MAP2K2 p.Phe213= (c.639C>T) in the general population?

MAP2K2 p.Phe213= (c.639C>T) is very rare (popmax 0.00902%, sas) (gnomAD).

MAP2K2 p.Phe213=

c.639C>T · rs727504818 · VCV179367

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00902%, sas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP -4.6	GERP -3.9
Overall
CADD	4.764	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00902% South Asian · 8/88,738 alleles

Filtering AF 0.00447% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00319%

Overall 0.00113% 18/1,599,672 alleles · very rare exomes 16/1,447,658 · genomes 2/152,014 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00902%	11,092
African / African-American	0.00134%	74,414
European (non-Finnish)	0.000767%	130,388

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.Phe213=
Coding: c.639C>T
MANE Select: NM_030662
dbSNP: rs727504818
Type: single nucleotide variant
Location: chr19:4101085 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 213: 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

Also linked: RASopathy

Similar variants

MAP2K2 p.Phe213fs Uncertain significance ★ same residue
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

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-phe213 (accessed [today's date]).

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