Is MAP2K2 p.Val202Met (c.604G>A) pathogenic?

MAP2K2 p.Val202Met (c.604G>A) is classified Conflicting classifications of pathogenicity in MAP2K2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-14). AlphaMissense: likely pathogenic (0.8618); Ultra-rare (popmax 0.0166%, mid); Associated with cardiofaciocutaneous syndrome 4.

What condition is associated with MAP2K2 p.Val202Met (c.604G>A)?

MAP2K2 p.Val202Met (c.604G>A) is associated with cardiofaciocutaneous syndrome 4, RASopathy (ClinVar).

How common is MAP2K2 p.Val202Met (c.604G>A) in the general population?

MAP2K2 p.Val202Met (c.604G>A) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about MAP2K2 p.Val202Met (c.604G>A)?

AlphaMissense predicts likely pathogenic (score 0.8618) — an in-silico prediction, not a clinical call.

MAP2K2 p.Val202Met

c.604G>A · rs769471250 · VCV40812

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.8618 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

cardiofaciocutaneous syndrome 4

Computational evidence

Protein change
AlphaMissense	0.8618	likely pathogenic
REVEL	0.582	indeterminate
SaProt	LLR -11.45	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.33 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 0.81, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 18 kb · p 1.4e-08 · regional, not allelic
Overall
CADD	28.9	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 0.0166% Middle Eastern · 1/6,036 alleles

Filtering AF 0.00443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00316%

Overall 0.00405% 65/1,605,590 alleles · ultra-rare exomes 55/1,454,256 · genomes 10/151,334 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,036
South Asian	0.00892%	11,212
Ashkenazi Jewishnot grpmax-eligible	0.00681%	14,675
Remaining individualsnot grpmax-eligible	0.00644%	15,527
East Asian	0.00451%	22,169
African / African-American	0.00403%	24,827
European (non-Finnish)	0.00383%	26,138

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.Val202Met
Coding: c.604G>A
MANE Select: NM_030662
dbSNP: rs769471250
Type: single nucleotide variant
Location: chr19:4101120 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 202: the protein kinase domain; a β-strand

Full MAP2K2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cardiofaciocutaneous syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: RASopathy

Similar variants

MAP2K2 p.Val202Gly Uncertain significance ★★ ⚠ same residue
MAP2K2 p.Val202Leu Uncertain significance ★ ⚠ 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-val202met (accessed [today's date]).

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