Is MAP2K2 p.Arg388Trp (c.1162C>T) pathogenic?

MAP2K2 p.Arg388Trp (c.1162C>T) is classified Benign in MAP2K2 (ClinVar, Expert panel, 11 submitters; last evaluated 2017-05-09). AlphaMissense: likely benign (0.1943); Rare (popmax 0.746%, afr); Associated with RASopathy.

What condition is associated with MAP2K2 p.Arg388Trp (c.1162C>T)?

MAP2K2 p.Arg388Trp (c.1162C>T) is associated with RASopathy, cardiofaciocutaneous syndrome 4, Noonan syndrome (ClinVar).

How common is MAP2K2 p.Arg388Trp (c.1162C>T) in the general population?

MAP2K2 p.Arg388Trp (c.1162C>T) is rare (popmax 0.746%, afr) (gnomAD).

What do computational predictors say about MAP2K2 p.Arg388Trp (c.1162C>T)?

AlphaMissense predicts likely benign (score 0.1943) — an in-silico prediction, not a clinical call.

MAP2K2 p.Arg388Trp

c.1162C>T · rs144383241 · VCV40843

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.1943 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.746%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

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.1162C>T (p.Arg388Trp) variant in the MAP2K2 gene is 0.125% for African chromosomes by the Exome Aggregation Consortium (25/2788 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). Additional case-level data available: SCV000204180.4; SCV000252871.4.

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

Computational evidence

Protein change
AlphaMissense	0.1943	likely benign
REVEL	0.396	indeterminate
SaProt	LLR -13.10	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP -3.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,766 bp · p 0.55 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.746% African / African-American · 548/73,466 alleles

Filtering AF 0.694% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.674%

Overall 0.0382% 595/1,555,980 alleles · rare exomes 286/1,403,656 · genomes 309/152,324 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.746%	134
Remaining individualsnot grpmax-eligible	0.0382%	2,621
Admixed American	0.0136%	7,369
Finnishnot grpmax-eligible	0.00169%	59,240
European (non-Finnish)	0.0013%	76,663
South Asian	0.00118%	84,498

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.Arg388Trp
Coding: c.1162C>T
MANE Select: NM_030662
dbSNP: rs144383241
Type: single nucleotide variant
Location: chr19:4090639 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB

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

Similar variants

MAP2K2 p.Arg388= Likely benign ★★ same residue
MAP2K2 p.Arg388Gln Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg388trp (accessed [today's date]).

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