Is MAP2K2 p.Ser222Pro (c.664T>C) pathogenic?

MAP2K2 p.Ser222Pro (c.664T>C) is classified Uncertain significance in MAP2K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-25). AlphaMissense: likely pathogenic (0.9996); Very rare (popmax 6.31e-05%); Associated with RASopathy.

What condition is associated with MAP2K2 p.Ser222Pro (c.664T>C)?

MAP2K2 p.Ser222Pro (c.664T>C) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Ser222Pro (c.664T>C) in the general population?

MAP2K2 p.Ser222Pro (c.664T>C) is very rare (popmax 6.31e-05%) (gnomAD).

What do computational predictors say about MAP2K2 p.Ser222Pro (c.664T>C)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

MAP2K2 p.Ser222Pro

c.664T>C · VCV3636797

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.31e-05%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic · top 3% in MAP2K2
REVEL	0.915	moderately pathogenic-leaning
SaProt	LLR -14.11	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 18 kb · p 1.4e-08 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.31e-05%

Overall 6.31e-05% 1/1,584,308 alleles · very rare exomes 1/1,432,116 · genomes 0/152,192 · joint denominator

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.Ser222Pro
Coding: c.664T>C
MANE Select: NM_030662
Type: single nucleotide variant
Location: chr19:4101060 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 222: the protein kinase domain; a modified residue (phosphoserine; by raf; alternate); an α-helix; a modified residue ((microbial infection) o-acetylserine; by yersinia yopj; alternate)

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.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
MAP2K2 p.Arg281Gln 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-ser222pro (accessed [today's date]).

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