Is MAP2K2 p.Arg397His (c.1190G>A) pathogenic?

MAP2K2 p.Arg397His (c.1190G>A) is classified Uncertain significance in MAP2K2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-14). AlphaMissense: likely benign (0.0823); Ultra-rare (popmax 0.0261%, sas); Associated with Cardiovascular phenotype.

What condition is associated with MAP2K2 p.Arg397His (c.1190G>A)?

MAP2K2 p.Arg397His (c.1190G>A) is associated with Cardiovascular phenotype, cardiofaciocutaneous syndrome 4, RASopathy (ClinVar).

How common is MAP2K2 p.Arg397His (c.1190G>A) in the general population?

MAP2K2 p.Arg397His (c.1190G>A) is ultra-rare (popmax 0.0261%, sas) (gnomAD).

What do computational predictors say about MAP2K2 p.Arg397His (c.1190G>A)?

AlphaMissense predicts likely benign (score 0.0823) — an in-silico prediction, not a clinical call.

MAP2K2 p.Arg397His

c.1190G>A · rs751040819 · VCV40844

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0823 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0261%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0823	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -7.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP -3.2, phastCons 0.99
Regional constraint	o/e 0.96	unconstrained · MANE · 8,766 bp · p 0.55 · regional, not allelic
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0261% South Asian · 22/84,154 alleles

Filtering AF 0.0177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0149%

Overall 0.00238% 37/1,551,380 alleles · ultra-rare exomes 37/1,399,040 · genomes 0/152,340 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0261%	3,825
Middle Eastern	0.0175%	5,718
Remaining individualsnot grpmax-eligible	0.00666%	15,024
East Asian	0.00244%	41,040
European (non-Finnish)	0.000784%	127,497

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.Arg397His
Coding: c.1190G>A
MANE Select: NM_030662
dbSNP: rs751040819
Type: single nucleotide variant
Location: chr19:4090611 (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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiofaciocutaneous syndrome 4 RASopathy

Similar variants

MAP2K2 p.Arg397Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
MAP2K2 p.Arg397Leu Uncertain significance ★ ⚠ same residue
MAP2K2 p.Arg397= Likely benign 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

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-arg397his (accessed [today's date]).

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