Is MAP2K2 p.Ser204Cys (c.611C>G) pathogenic?

MAP2K2 p.Ser204Cys (c.611C>G) is classified Uncertain significance in MAP2K2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-01). AlphaMissense: likely benign (0.2394); Ultra-rare (popmax 0.0165%, mid); Associated with RASopathy.

What condition is associated with MAP2K2 p.Ser204Cys (c.611C>G)?

MAP2K2 p.Ser204Cys (c.611C>G) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Ser204Cys (c.611C>G) in the general population?

MAP2K2 p.Ser204Cys (c.611C>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about MAP2K2 p.Ser204Cys (c.611C>G)?

AlphaMissense predicts likely benign (score 0.2394) — an in-silico prediction, not a clinical call.

MAP2K2 p.Ser204Cys

c.611C>G · rs775668076 · VCV1488119

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2394 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.2394	likely benign
REVEL	0.299	indeterminate
SaProt	LLR -11.93	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 7.5	GERP -0.52, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 18 kb · p 1.4e-08 · regional, not allelic
Overall
CADD	24.0	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 0.0165% Middle Eastern · 1/6,056 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00168% 27/1,607,426 alleles · ultra-rare exomes 26/1,455,318 · genomes 1/152,108 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,056
European (non-Finnish)	0.00204%	49,050
Admixed American	0.00169%	59,238
African / African-American	0.00134%	74,722

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.Ser204Cys
Coding: c.611C>G
MANE Select: NM_030662
dbSNP: rs775668076
Type: single nucleotide variant
Location: chr19:4101113 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 204: 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

Similar variants

MAP2K2 p.Ser204= Likely benign ★★ 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
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-ser204cys (accessed [today's date]).

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