Is MAP2K2 p.Val305Ile (c.913G>A) pathogenic?

MAP2K2 p.Val305Ile (c.913G>A) is classified Conflicting classifications of pathogenicity in MAP2K2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-30). AlphaMissense: likely benign (0.0677); Ultra-rare (popmax 0.017%, mid); Associated with Cardiovascular phenotype.

What condition is associated with MAP2K2 p.Val305Ile (c.913G>A)?

MAP2K2 p.Val305Ile (c.913G>A) is associated with Cardiovascular phenotype, cardiofaciocutaneous syndrome 4, RASopathy (ClinVar).

How common is MAP2K2 p.Val305Ile (c.913G>A) in the general population?

MAP2K2 p.Val305Ile (c.913G>A) is ultra-rare (popmax 0.017%, mid) (gnomAD).

What do computational predictors say about MAP2K2 p.Val305Ile (c.913G>A)?

AlphaMissense predicts likely benign (score 0.0677) — an in-silico prediction, not a clinical call.

MAP2K2 p.Val305Ile

c.913G>A · rs730880509 · VCV180903

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0677 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.017%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0677	likely benign
REVEL	0.151	moderately benign-leaning
SaProt	LLR -7.05	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 -0.1	GERP -3.9, phastCons 0.84
Regional constraint	o/e 0.96	unconstrained · MANE · 8,766 bp · p 0.55 · regional, not allelic
Overall
CADD	10.45	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 0.017% Middle Eastern · 1/5,894 alleles

Filtering AF 0.00197% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00169%

Overall 0.00225% 36/1,601,666 alleles · ultra-rare exomes 35/1,449,452 · genomes 1/152,214 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.017%	5,894
Remaining individualsnot grpmax-eligible	0.00323%	30,983
European (non-Finnish)	0.00272%	36,724
South Asian	0.00111%	89,692

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.Val305Ile
Coding: c.913G>A
MANE Select: NM_030662
dbSNP: rs730880509
Type: single nucleotide variant
Location: chr19:4099207 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 305: the protein kinase domain; the 'disordered' region

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.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
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-val305ile (accessed [today's date]).

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