Is MAP2K1 p.Ile216= (c.648C>T) pathogenic?

MAP2K1 p.Ile216= (c.648C>T) is classified Benign in MAP2K1 (ClinVar, Expert panel, 9 submitters; last evaluated 2017-05-09). Rare (popmax 0.407%, afr); Associated with RASopathy.

What condition is associated with MAP2K1 p.Ile216= (c.648C>T)?

MAP2K1 p.Ile216= (c.648C>T) is associated with RASopathy, Noonan syndrome and Noonan-related syndrome (ClinVar).

How common is MAP2K1 p.Ile216= (c.648C>T) in the general population?

MAP2K1 p.Ile216= (c.648C>T) is rare (popmax 0.407%, afr) (gnomAD).

MAP2K1 p.Ile216=

c.648C>T · rs148968935 · VCV44590

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.407%, afr)

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.648C>T (p.Ile216=) variant in the MAP2K1 gene is 0.274% (38/10402) of African 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.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.4	GERP -4.4
Overall
CADD	8.851	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.407% African / African-American · 305/75,028 alleles

Filtering AF 0.369% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.354%

Overall 0.0208% 335/1,614,020 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.407%	246
Remaining individualsnot grpmax-eligible	0.0176%	5,681
Admixed American	0.0133%	7,502
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
East Asian	0.00223%	44,890
European (non-Finnish)	0.000763%	131,111

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.Ile216=
Coding: c.648C>T
MANE Select: NM_002755
dbSNP: rs148968935
Type: single nucleotide variant
Location: chr15:66481834 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI 0.97 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 84.05 · 99 PDB
Residue 216: 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.Ile216Thr Uncertain significance ★ ⚠ same residue
MAP2K1 p.Ile216Val 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-ile216 (accessed [today's date]).

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