Is MAP2K1 p.Ala268= (c.804C>G) pathogenic?

MAP2K1 p.Ala268= (c.804C>G) is classified Benign in MAP2K1 (ClinVar, Expert panel, 10 submitters; last evaluated 2017-05-09). Low-frequency (popmax 1.15%, sas); Associated with RASopathy.

What condition is associated with MAP2K1 p.Ala268= (c.804C>G)?

MAP2K1 p.Ala268= (c.804C>G) is associated with RASopathy, Noonan syndrome and Noonan-related syndrome (ClinVar).

How common is MAP2K1 p.Ala268= (c.804C>G) in the general population?

MAP2K1 p.Ala268= (c.804C>G) is low-frequency (popmax 1.15%, sas) (gnomAD).

MAP2K1 p.Ala268=

c.804C>G · rs371652992 · VCV44592

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.15%, sas)

Conditions

RASopathy

ClinGen expert panel — RASopathy VCEP

Benign for RASopathy. Applied ACMG criteria (verbatim):

BA1

Curation rationale (ClinGen, verbatim)

The filtering allele frequency of the c.804C>G (p.Ala268=) variant in the MAP2K1 gene is 1.234% (228/16512) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.467	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 2, phastCons 1
Overall
CADD	13.15	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.15% South Asian · 1,047/91,064 alleles

Filtering AF 1.09% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.07%

Overall 0.0688% 1,110/1,613,972 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	1.15%	87
Remaining individualsnot grpmax-eligible	0.0656%	1,524
Admixed American	0.00333%	30,003
European (non-Finnish)	0.00161%	62,104
African / African-American	0.00133%	75,026

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.Ala268=
Coding: c.804C>G
MANE Select: NM_002755
dbSNP: rs371652992
Type: single nucleotide variant
Location: chr15:66485100 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI 0.97 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 84.05 · 99 PDB
Residue 268: the protein kinase domain; an α-helix

Full MAP2K1 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

Also linked: Noonan syndrome and Noonan-related syndrome

Similar variants

MAP2K1 p.Ala268Val Uncertain significance ★★ ⚠ same residue
MAP2K1 p.Ala268Thr Uncertain significance ★ ⚠ same residue
MAP2K1 p.Arg108Leu Likely pathogenic ★★★ same condition
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

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-ala268 (accessed [today's date]).

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