Is MAP2K2 p.Leu260= (c.778C>T) pathogenic?

MAP2K2 p.Leu260= (c.778C>T) is classified Likely benign in MAP2K2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-11). Ultra-rare (popmax 0.0297%, sas); Associated with Cardiovascular phenotype.

What condition is associated with MAP2K2 p.Leu260= (c.778C>T)?

MAP2K2 p.Leu260= (c.778C>T) is associated with Cardiovascular phenotype, RASopathy (ClinVar).

How common is MAP2K2 p.Leu260= (c.778C>T) in the general population?

MAP2K2 p.Leu260= (c.778C>T) is ultra-rare (popmax 0.0297%, sas) (gnomAD).

MAP2K2 p.Leu260=

c.778C>T · rs766528759 · VCV702500

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0297%, sas)

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 5.8	GERP -1.9, phastCons 1
Overall
CADD	10.82	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0297% South Asian · 27/90,792 alleles

Filtering AF 0.0209% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.018%

Overall 0.00199% 32/1,611,344 alleles · ultra-rare exomes 31/1,459,134 · genomes 1/152,210 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0297%	3,363
Remaining individualsnot grpmax-eligible	0.00321%	31,200
African / African-American	0.00133%	74,908
European (non-Finnish)	0.00017%	589,612

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.Leu260=
Coding: c.778C>T
MANE Select: NM_030662
dbSNP: rs766528759
Type: single nucleotide variant
Location: chr19:4099342 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 260: 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: RASopathy

Similar variants

MAP2K2 p.Glu207Lys Likely pathogenic ★★★ same condition
MAP2K2 p.Phe57Cys 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
MAP2K2 p.Arg281Gln 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-leu260 (accessed [today's date]).

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