Is MAP2K2 p.Pro340= (c.1020C>T) pathogenic?

MAP2K2 p.Pro340= (c.1020C>T) is classified Benign in MAP2K2 (ClinVar, Expert panel, 9 submitters; last evaluated 2017-05-09). Rare (popmax 0.371%, sas); Associated with RASopathy.

What condition is associated with MAP2K2 p.Pro340= (c.1020C>T)?

MAP2K2 p.Pro340= (c.1020C>T) is associated with RASopathy, Noonan syndrome and Noonan-related syndrome (ClinVar).

How common is MAP2K2 p.Pro340= (c.1020C>T) in the general population?

MAP2K2 p.Pro340= (c.1020C>T) is rare (popmax 0.371%, sas) (gnomAD).

MAP2K2 p.Pro340=

c.1020C>T · rs192389729 · VCV46226

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.371%, 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.1020C>T (p.Pro340=) variant in the MAP2K2 gene is 0.262% (29/7910) 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 -0.89	GERP -3.5, phastCons 0.003
Overall
CADD	10.51	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.371% South Asian · 312/84,044 alleles

Filtering AF 0.337% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.324%

Overall 0.0259% 402/1,551,270 alleles · rare exomes 366/1,398,990 · genomes 36/152,280 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.371%	269
Middle Eastern	0.0835%	1,197
Ashkenazi Jewishnot grpmax-eligible	0.0349%	2,864
Remaining individualsnot grpmax-eligible	0.03%	3,339
Admixed American	0.0216%	4,635
European (non-Finnish)	0.00401%	24,931

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.Pro340=
Coding: c.1020C>T
MANE Select: NM_030662
dbSNP: rs192389729
Type: single nucleotide variant
Location: chr19:4095414 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 340: 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

Also linked: Noonan syndrome and Noonan-related syndrome

Similar variants

MAP2K2 p.Pro340Leu Uncertain significance ★★ ⚠ same residue
MAP2K2 p.Pro340Arg Uncertain significance ★ ⚠ same residue
MAP2K2 p.Pro340Ser 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

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-pro340 (accessed [today's date]).

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