Is MAP2K2 p.Lys273Arg (c.818A>G) pathogenic?

MAP2K2 p.Lys273Arg (c.818A>G) is classified Likely benign in MAP2K2 (ClinVar, Expert panel, 7 submitters; last evaluated 2017-05-09). AlphaMissense: likely benign (0.0646); Ultra-rare (popmax 0.0287%, amr); Associated with RASopathy.

What condition is associated with MAP2K2 p.Lys273Arg (c.818A>G)?

MAP2K2 p.Lys273Arg (c.818A>G) is associated with RASopathy, cardiofaciocutaneous syndrome 4 (ClinVar).

How common is MAP2K2 p.Lys273Arg (c.818A>G) in the general population?

MAP2K2 p.Lys273Arg (c.818A>G) is ultra-rare (popmax 0.0287%, amr) (gnomAD).

What do computational predictors say about MAP2K2 p.Lys273Arg (c.818A>G)?

AlphaMissense predicts likely benign (score 0.0646) — an in-silico prediction, not a clinical call.

MAP2K2 p.Lys273Arg

c.818A>G · rs539555837 · VCV40824

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0646 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0287%, amr)

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.818A>G (p.Lys273Arg) variant in the MAP2K2 gene is 0.0368% (6/7088) of Latino 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	0.0646	likely benign
REVEL	0.256	benign-leaning
SaProt	LLR -7.35	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 5	GERP 0.99, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,766 bp · p 0.55 · regional, not allelic
Overall
CADD	21.3	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 0.0287% Admixed American · 17/59,146 alleles

Filtering AF 0.0182% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0149%

Overall 0.00317% 51/1,607,610 alleles · ultra-rare exomes 46/1,455,292 · genomes 5/152,318 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0287%	3,479
Middle Eastern	0.0165%	6,056
Remaining individualsnot grpmax-eligible	0.00321%	31,128
European (non-Finnish)	0.00263%	37,983

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.Lys273Arg
Coding: c.818A>G
MANE Select: NM_030662
dbSNP: rs539555837
Type: single nucleotide variant
Location: chr19:4099302 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 273: 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: cardiofaciocutaneous syndrome 4

Similar variants

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
MAP2K2 p.Arg231Leu 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-lys273arg (accessed [today's date]).

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