Is MAP2K2 p.Ile75= (c.225C>T) pathogenic?

MAP2K2 p.Ile75= (c.225C>T) is classified Benign in MAP2K2 (ClinVar, Expert panel, 7 submitters; last evaluated 2017-05-09). Rare (popmax 0.142%, sas); Associated with RASopathy.

What condition is associated with MAP2K2 p.Ile75= (c.225C>T)?

MAP2K2 p.Ile75= (c.225C>T) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Ile75= (c.225C>T) in the general population?

MAP2K2 p.Ile75= (c.225C>T) is rare (popmax 0.142%, sas) (gnomAD).

MAP2K2 p.Ile75=

c.225C>T · rs561400866 · VCV448952

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.142%, sas)

Conditions

RASopathy

ClinGen expert panel — RASopathy VCEP

Benign for RASopathy. Applied ACMG criteria (verbatim):

BA1

Curation rationale (ClinGen, verbatim)

The filtering allele frequency of the c.225C>T (p.Ile75=) variant in the MAP2K2 gene is 0.08% (20/16508) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

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 3.9	GERP -0.38, phastCons 1
Overall
CADD	11.68	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.142% South Asian · 129/91,090 alleles

Filtering AF 0.122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.114%

Overall 0.00892% 144/1,614,174 alleles · rare exomes 139/1,461,834 · genomes 5/152,340 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.142%	706
Remaining individualsnot grpmax-eligible	0.0176%	5,683
Admixed American	0.00167%	60,022
African / African-American	0.00133%	75,058
European (non-Finnish)	0.000169%	590,023

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.Ile75=
Coding: c.225C>T
MANE Select: NM_030662
dbSNP: rs561400866
Type: single nucleotide variant
Location: chr19:4117497 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 75: the protein kinase domain; a β-strand

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.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-ile75 (accessed [today's date]).

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