Is MAP2K2 p.Val283Leu (c.847G>T) pathogenic?

MAP2K2 p.Val283Leu (c.847G>T) is classified Likely benign in MAP2K2 (ClinVar, Expert panel, 3 submitters; last evaluated 2017-05-09). AlphaMissense: likely benign (0.0884); Ultra-rare (popmax 0.0135%, eas); Associated with RASopathy.

What condition is associated with MAP2K2 p.Val283Leu (c.847G>T)?

MAP2K2 p.Val283Leu (c.847G>T) is associated with RASopathy, cardiofaciocutaneous syndrome 4 (ClinVar).

How common is MAP2K2 p.Val283Leu (c.847G>T) in the general population?

MAP2K2 p.Val283Leu (c.847G>T) is ultra-rare (popmax 0.0135%, eas) (gnomAD).

What do computational predictors say about MAP2K2 p.Val283Leu (c.847G>T)?

AlphaMissense predicts likely benign (score 0.0884) — an in-silico prediction, not a clinical call.

MAP2K2 p.Val283Leu

c.847G>T · rs185999703 · VCV448950

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0884 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0135%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

ClinGen expert panel — RASopathy VCEP

Likely Benign for RASopathy. Applied ACMG criteria (verbatim):

BS1

Curation rationale (ClinGen, verbatim)

The filtering allele frequency of the c.847G>T (p.Val283Leu) variant in the MAP2K2 gene is 0.0448% (6/5824) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581)

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

Computational evidence

Protein change
AlphaMissense	0.0884	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -6.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.7	GERP -3.5
Regional constraint	o/e 0.96	unconstrained · MANE · 8,766 bp · p 0.55 · regional, not allelic
Overall
CADD	11.15	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 0.0135% East Asian · 6/44,562 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00396%

Overall 0.000436% 7/1,605,934 alleles · ultra-rare exomes 5/1,453,606 · genomes 2/152,328 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0135%	7,427
European (non-Finnish)	8.5e-05%	1,176,732

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.Val283Leu
Coding: c.847G>T
MANE Select: NM_030662
dbSNP: rs185999703
Type: single nucleotide variant
Location: chr19:4099273 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 283: 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

Similar variants

MAP2K2 p.Val283Met 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
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-val283leu (accessed [today's date]).

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