Is MAP2K2 p.Ile220= (c.660C>T) pathogenic?

MAP2K2 p.Ile220= (c.660C>T) is classified Likely benign in MAP2K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-15). Very rare (popmax 0.00232%, eas); Associated with RASopathy.

What condition is associated with MAP2K2 p.Ile220= (c.660C>T)?

MAP2K2 p.Ile220= (c.660C>T) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Ile220= (c.660C>T) in the general population?

MAP2K2 p.Ile220= (c.660C>T) is very rare (popmax 0.00232%, eas) (gnomAD).

MAP2K2 p.Ile220=

c.660C>T · rs10250 · VCV2913078

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00232%, eas)

Conditions

RASopathy

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 -1.9	GERP -3.2
Overall
CADD	10.92	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00232% East Asian · 1/43,058 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000315% 5/1,585,702 alleles · very rare exomes 5/1,433,788 · genomes 0/151,914 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00232%	43,058
European (non-Finnish)	0.000343%	291,600

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.Ile220=
Coding: c.660C>T
MANE Select: NM_030662
dbSNP: rs10250
Type: single nucleotide variant
Location: chr19:4101064 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 220: the protein kinase domain; an α-helix

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

Disease context

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

Similar variants

MAP2K2 p.Ile220Thr Uncertain significance ★ same residue
MAP2K2 p.Ile220Val Likely benign ★ ⚠ 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

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-ile220 (accessed [today's date]).

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