Is MAP2K2 p.Asn335= (c.1005C>T) pathogenic?

MAP2K2 p.Asn335= (c.1005C>T) is classified Conflicting classifications of pathogenicity in MAP2K2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-09-23). Ultra-rare (popmax 0.0155%, sas); Associated with Noonan syndrome and Noonan-related syndrome.

What condition is associated with MAP2K2 p.Asn335= (c.1005C>T)?

MAP2K2 p.Asn335= (c.1005C>T) is associated with Noonan syndrome and Noonan-related syndrome, RASopathy (ClinVar).

How common is MAP2K2 p.Asn335= (c.1005C>T) in the general population?

MAP2K2 p.Asn335= (c.1005C>T) is ultra-rare (popmax 0.0155%, sas) (gnomAD).

MAP2K2 p.Asn335=

c.1005C>T · rs587781028 · VCV138162

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0155%, sas)

Conditions

Noonan syndrome and Noonan-related syndrome

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 -4.2	GERP -3.5
Overall
CADD	0.746	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0155% South Asian · 13/84,058 alleles

Filtering AF 0.0091% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.0049% 76/1,551,242 alleles · ultra-rare exomes 69/1,399,050 · genomes 7/152,192 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0155%	6,466
African / African-American	0.00548%	18,263
European (non-Finnish)	0.00471%	21,238
Admixed American	0.00392%	25,482
Remaining individualsnot grpmax-eligible	0.00333%	30,036
East Asian	0.00244%	40,922

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.Asn335=
Coding: c.1005C>T
MANE Select: NM_030662
dbSNP: rs587781028
Type: single nucleotide variant
Location: chr19:4095429 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 335: the protein kinase domain; a turn

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

Disease context

Noonan syndrome and Noonan-related syndrome — 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-asn335 (accessed [today's date]).

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