Is MAP2K2 p.Thr398= (c.1194C>T) pathogenic?

MAP2K2 p.Thr398= (c.1194C>T) is classified Benign in MAP2K2 (ClinVar, Expert panel, 7 submitters; last evaluated 2017-05-09). Ultra-rare (popmax 0.0352%, amr); Associated with RASopathy.

What condition is associated with MAP2K2 p.Thr398= (c.1194C>T)?

MAP2K2 p.Thr398= (c.1194C>T) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Thr398= (c.1194C>T) in the general population?

MAP2K2 p.Thr398= (c.1194C>T) is ultra-rare (popmax 0.0352%, amr) (gnomAD).

MAP2K2 p.Thr398=

c.1194C>T · rs144850779 · VCV40846

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0352%, amr)

Conditions

RASopathy

ClinGen expert panel — RASopathy VCEP

Benign for RASopathy. Applied ACMG criteria (verbatim):

BA1

Curation rationale (ClinGen, verbatim)

The filtering allele frequency of the c.1194C>T (p.Thr398=) variant in the MAP2K2 gene is 0.159% (19/7836) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

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 -6	GERP -3.2
Overall
CADD	0.92	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0352% Admixed American · 18/51,082 alleles

Filtering AF 0.0227% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0188%

Overall 0.0192% 297/1,550,870 alleles · ultra-rare exomes 263/1,398,640 · genomes 34/152,230 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.663%	151
Remaining individualsnot grpmax-eligible	0.05%	2,002
Admixed Americangrpmax	0.0352%	2,838
African / African-American	0.00547%	18,279
European (non-Finnish)	0.00471%	21,245
Finnishnot grpmax-eligible	0.0017%	58,930

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr398=
Coding: c.1194C>T
MANE Select: NM_030662
dbSNP: rs144850779
Type: single nucleotide variant
Location: chr19:4090607 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB

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.Thr398Pro Uncertain significance ★★ ⚠ same residue
MAP2K2 p.Thr398Ser 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

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-thr398 (accessed [today's date]).

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