Is MAP2K1 p.Pro346= (c.1038C>T) pathogenic?

MAP2K1 p.Pro346= (c.1038C>T) is classified Likely benign in MAP2K1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-01). Very rare (popmax 0.00933%, afr); Associated with Cardiovascular phenotype.

What condition is associated with MAP2K1 p.Pro346= (c.1038C>T)?

MAP2K1 p.Pro346= (c.1038C>T) is associated with Cardiovascular phenotype, RASopathy (ClinVar).

How common is MAP2K1 p.Pro346= (c.1038C>T) in the general population?

MAP2K1 p.Pro346= (c.1038C>T) is very rare (popmax 0.00933%, afr) (gnomAD).

MAP2K1 p.Pro346=

c.1038C>T · rs547178339 · VCV1087058

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00933%, afr)

Conditions

Cardiovascular phenotype

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 -5.7	GERP -4.4
Overall
CADD	3.57	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00933% African / African-American · 7/75,034 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00308%

Overall 0.00167% 27/1,613,854 alleles · very rare exomes 19/1,461,562 · genomes 8/152,292 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0236%	4,229
African / African-Americangrpmax	0.00933%	10,719
South Asian	0.00439%	22,768
Remaining individualsnot grpmax-eligible	0.0032%	31,249
Admixed American	0.00167%	60,016
European (non-Finnish)	0.000509%	196,624

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: MAP2K1
Protein: p.Pro346=
Coding: c.1038C>T
MANE Select: NM_002755
dbSNP: rs547178339
Type: single nucleotide variant
Location: chr15:66489733 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI 0.97 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 84.05 · 99 PDB
Residue 346: the protein kinase domain; a turn

Full MAP2K1 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: RASopathy

Similar variants

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MAP2K1 p.Asn122Asp Pathogenic ★★★ ⚠ same condition
MAP2K1 p.Asp67Asn Pathogenic ★★★ same condition
MAP2K1 p.Glu203Gly Pathogenic ★★★ same condition
MAP2K1 p.Leu42Arg Likely pathogenic ★★★ same condition
MAP2K1 p.Leu42Phe Pathogenic ★★★ same condition
MAP2K1 p.Leu92Arg Pathogenic ★★★ same condition
MAP2K1 p.Lys57Gln 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/map2k1-p-pro346 (accessed [today's date]).

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