Is MAP2K2 p.Arg388Gln (c.1163G>A) pathogenic?

MAP2K2 p.Arg388Gln (c.1163G>A) is classified Conflicting classifications of pathogenicity in MAP2K2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-12). AlphaMissense: likely benign (0.0693); Ultra-rare (popmax 0.029%, eas); Associated with cardiofaciocutaneous syndrome 4.

What condition is associated with MAP2K2 p.Arg388Gln (c.1163G>A)?

MAP2K2 p.Arg388Gln (c.1163G>A) is associated with cardiofaciocutaneous syndrome 4, RASopathy (ClinVar).

How common is MAP2K2 p.Arg388Gln (c.1163G>A) in the general population?

MAP2K2 p.Arg388Gln (c.1163G>A) is ultra-rare (popmax 0.029%, eas) (gnomAD).

What do computational predictors say about MAP2K2 p.Arg388Gln (c.1163G>A)?

AlphaMissense predicts likely benign (score 0.0693) — an in-silico prediction, not a clinical call.

MAP2K2 p.Arg388Gln

c.1163G>A · rs749615795 · VCV1005324

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0693 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.029%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cardiofaciocutaneous syndrome 4

Computational evidence

Protein change
AlphaMissense	0.0693	likely benign
REVEL	0.183	benign-leaning
SaProt	LLR -6.93	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 3.1	GERP 1.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,766 bp · p 0.55 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.029% East Asian · 12/41,382 alleles

Filtering AF 0.0167% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.013%

Overall 0.00315% 49/1,555,678 alleles · ultra-rare exomes 45/1,403,498 · genomes 4/152,180 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.029%	3,449
Remaining individualsnot grpmax-eligible	0.00664%	15,062
South Asian	0.00355%	28,168
European (non-Finnish)	0.00235%	42,587
Admixed American	0.00194%	51,546
Finnishnot grpmax-eligible	0.00169%	59,226
African / African-American	0.00136%	73,316

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.Arg388Gln
Coding: c.1163G>A
MANE Select: NM_030662
dbSNP: rs749615795
Type: single nucleotide variant
Location: chr19:4090638 (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

cardiofaciocutaneous syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: RASopathy

Similar variants

MAP2K2 p.Arg388Trp Benign ★★★ ⚠ same residue
MAP2K2 p.Arg388= 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
MAP2K2 p.Tyr134His 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-arg388gln (accessed [today's date]).

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