Is MAP2K2 p.Val346Ile (c.1036G>A) pathogenic?

MAP2K2 p.Val346Ile (c.1036G>A) is classified Uncertain significance in MAP2K2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-05-30). AlphaMissense: likely benign (0.1748); Very rare (popmax 0.00137%, afr); Associated with Cardiovascular phenotype.

What condition is associated with MAP2K2 p.Val346Ile (c.1036G>A)?

MAP2K2 p.Val346Ile (c.1036G>A) is associated with Cardiovascular phenotype, cardiofaciocutaneous syndrome 4, RASopathy (ClinVar).

How common is MAP2K2 p.Val346Ile (c.1036G>A) in the general population?

MAP2K2 p.Val346Ile (c.1036G>A) is very rare (popmax 0.00137%, afr) (gnomAD).

What do computational predictors say about MAP2K2 p.Val346Ile (c.1036G>A)?

AlphaMissense predicts likely benign (score 0.1748) — an in-silico prediction, not a clinical call.

MAP2K2 p.Val346Ile

c.1036G>A · rs1015139062 · VCV372640

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1748 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00137%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1748	likely benign
REVEL	0.347	indeterminate
SaProt	LLR -8.83	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.66, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,766 bp · p 0.55 · regional, not allelic
Overall
CADD	27.4	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 0.00137% African / African-American · 1/73,168 alleles

Overall 0.000129% 2/1,551,242 alleles · very rare exomes 2/1,398,938 · genomes 0/152,304 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00166%	60,106
African / African-Americangrpmax	0.00137%	73,168

Remaining individuals 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.Val346Ile
Coding: c.1036G>A
MANE Select: NM_030662
dbSNP: rs1015139062
Type: single nucleotide variant
Location: chr19:4095398 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 346: the protein kinase domain; an α-helix

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-val346ile (accessed [today's date]).

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