Is MAP2K2 p.Ser306= (c.918C>T) pathogenic?

MAP2K2 p.Ser306= (c.918C>T) is classified Conflicting classifications of pathogenicity in MAP2K2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-20). Very rare (popmax 0.00669%, afr); Associated with RASopathy.

What condition is associated with MAP2K2 p.Ser306= (c.918C>T)?

MAP2K2 p.Ser306= (c.918C>T) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Ser306= (c.918C>T) in the general population?

MAP2K2 p.Ser306= (c.918C>T) is very rare (popmax 0.00669%, afr) (gnomAD).

MAP2K2 p.Ser306=

c.918C>T · rs777196833 · VCV477729

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00669%, afr)

Conditions

RASopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.69	GERP -3.9
Overall
CADD	7.282	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00669% African / African-American · 5/74,784 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.0015% 24/1,599,690 alleles · very rare exomes 20/1,447,480 · genomes 4/152,210 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00669%	14,957
Remaining individualsnot grpmax-eligible	0.00323%	30,943
European (non-Finnish)	0.00136%	73,398
South Asian	0.00112%	89,512

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.Ser306=
Coding: c.918C>T
MANE Select: NM_030662
dbSNP: rs777196833
Type: single nucleotide variant
Location: chr19:4099202 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 306: the protein kinase domain; a modified residue (phosphoserine); the 'disordered' region

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.Ser306Ile Uncertain significance ★ ⚠ 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-ser306 (accessed [today's date]).

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