Is MAP2K2 p.Thr230= (c.690G>A) pathogenic?

MAP2K2 p.Thr230= (c.690G>A) is classified Benign in MAP2K2 (ClinVar, Expert panel, 9 submitters; last evaluated 2018-11-15). Ultra-rare (popmax 0.0994%, amr); Associated with RASopathy.

What condition is associated with MAP2K2 p.Thr230= (c.690G>A)?

MAP2K2 p.Thr230= (c.690G>A) is associated with RASopathy, cardiofaciocutaneous syndrome 4, Noonan syndrome and Noonan-related syndrome (ClinVar).

How common is MAP2K2 p.Thr230= (c.690G>A) in the general population?

MAP2K2 p.Thr230= (c.690G>A) is ultra-rare (popmax 0.0994%, amr) (gnomAD).

MAP2K2 p.Thr230=

c.690G>A · rs201287884 · VCV138159

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0994%, amr)

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.690G>A (p.Thr230=) variant in the MAP2K2 gene is 0.1273% for Latino chromosomes by the Exome Aggregation Consortium (3/642 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1).

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 -20	GERP -3.9
Overall
CADD	0.108	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0994% Admixed American · 52/52,340 alleles

Filtering AF 0.0777% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0701%

Overall 0.0119% 186/1,564,098 alleles · ultra-rare exomes 174/1,412,080 · genomes 12/152,018 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0994%	1,007
Middle Eastern	0.0409%	2,444
South Asian	0.0364%	2,749
African / African-American	0.0109%	9,193
European (non-Finnish)	0.00745%	13,431
Remaining individualsnot grpmax-eligible	0.0066%	15,162
East Asian	0.00478%	20,925
Finnishnot grpmax-eligible	0.00164%	60,808

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.Thr230=
Coding: c.690G>A
MANE Select: NM_030662
dbSNP: rs201287884
Type: single nucleotide variant
Location: chr19:4101034 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 230: the protein kinase domain

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

Also linked: cardiofaciocutaneous syndrome 4 Noonan syndrome and Noonan-related syndrome

Similar variants

MAP2K2 p.Thr230Met Uncertain significance ★★ ⚠ same residue
MAP2K2 p.Glu207Lys Likely pathogenic ★★★ same condition
MAP2K2 p.Phe57Cys Pathogenic ★★★ same condition
MAP2K2 p.Phe57Val 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-thr230 (accessed [today's date]).

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