Is MAP2K2 p.Leu105= (c.315T>G) pathogenic?

MAP2K2 p.Leu105= (c.315T>G) is classified Likely benign in MAP2K2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-06-22). Ultra-rare (popmax 0.0165%, mid); Associated with RASopathy.

What condition is associated with MAP2K2 p.Leu105= (c.315T>G)?

MAP2K2 p.Leu105= (c.315T>G) is associated with RASopathy (ClinVar).

How common is MAP2K2 p.Leu105= (c.315T>G) in the general population?

MAP2K2 p.Leu105= (c.315T>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

MAP2K2 p.Leu105=

c.315T>G · rs761590887 · VCV738007

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

RASopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.083	GERP -3.3, phastCons 0.91
Overall
CADD	8.801	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,076 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.0018% 29/1,609,286 alleles · ultra-rare exomes 27/1,457,190 · genomes 2/152,096 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,076
South Asian	0.0132%	7,585
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,586
Remaining individualsnot grpmax-eligible	0.0016%	62,342
African / African-American	0.00134%	74,854
European (non-Finnish)	0.0011%	90,514

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.Leu105=
Coding: c.315T>G
MANE Select: NM_030662
dbSNP: rs761590887
Type: single nucleotide variant
Location: chr19:4110644 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 105: the protein kinase domain

Full MAP2K2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

RASopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAP2K2 p.Leu105Val Uncertain significance ★ ⚠ same residue
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

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-leu105 (accessed [today's date]).

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