Is MAP2K2 p.Thr339= (c.1017C>T) pathogenic?

MAP2K2 p.Thr339= (c.1017C>T) is classified Conflicting classifications of pathogenicity in MAP2K2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-06-12). Very rare (popmax 0.000698%, nfe); Associated with cardiofaciocutaneous syndrome 4.

What condition is associated with MAP2K2 p.Thr339= (c.1017C>T)?

MAP2K2 p.Thr339= (c.1017C>T) is associated with cardiofaciocutaneous syndrome 4 (ClinVar).

How common is MAP2K2 p.Thr339= (c.1017C>T) in the general population?

MAP2K2 p.Thr339= (c.1017C>T) is very rare (popmax 0.000698%, nfe) (gnomAD).

MAP2K2 p.Thr339=

c.1017C>T · rs1205517548 · VCV1747506

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000698%, nfe)

Conditions

cardiofaciocutaneous syndrome 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP -3.5, phastCons 1
Overall
CADD	9.661	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000698% European (non-Finnish) · 8/1,146,878 alleles

Filtering AF 0.0003% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000217%

Overall 0.000516% 8/1,551,250 alleles · very rare exomes 5/1,399,068 · genomes 3/152,182 · 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.Thr339=
Coding: c.1017C>T
MANE Select: NM_030662
dbSNP: rs1205517548
Type: single nucleotide variant
Location: chr19:4095417 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 339: the protein kinase domain

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

Similar variants

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
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-thr339 (accessed [today's date]).

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