Is MAP2K1 p.Leu251= (c.753G>A) pathogenic?

MAP2K1 p.Leu251= (c.753G>A) is classified Likely benign in MAP2K1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-12-26). Very rare (popmax 0.000339%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with MAP2K1 p.Leu251= (c.753G>A)?

MAP2K1 p.Leu251= (c.753G>A) is associated with Cardiovascular phenotype (ClinVar).

How common is MAP2K1 p.Leu251= (c.753G>A) in the general population?

MAP2K1 p.Leu251= (c.753G>A) is very rare (popmax 0.000339%, nfe) (gnomAD).

MAP2K1 p.Leu251=

c.753G>A · rs2140674249 · VCV1759435

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.04	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.8	GERP -4
Overall
CADD	1.852	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,032 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,902 alleles · very rare exomes 4/1,461,574 · genomes 0/152,328 · joint denominator

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.Leu251=
Coding: c.753G>A
MANE Select: NM_002755
dbSNP: rs2140674249
Type: single nucleotide variant
Location: chr15:66485049 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI 0.97 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 84.05 · 99 PDB
Residue 251: the protein kinase domain; an α-helix

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

Similar variants

MAP2K1 p.Ala268Val Uncertain significance ★★ ⚠ same condition
MAP2K1 p.Ala32Val Uncertain significance ★★ ⚠ same condition
MAP2K1 p.Arg108Gln Uncertain significance ★★ ⚠ same condition
MAP2K1 p.Arg291Gly Uncertain significance ★★ ⚠ same condition
MAP2K1 p.Asp217Asn Uncertain significance ★★ ⚠ same condition
MAP2K1 p.Asp267Glu Uncertain significance ★★ ⚠ same condition
MAP2K1 p.Ile107Val Uncertain significance ★★ ⚠ same condition
MAP2K1 p.Ile317Thr 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/map2k1-p-leu251 (accessed [today's date]).

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