Is MAP2K2 p.Arg313Gln (c.938G>A) pathogenic?

MAP2K2 p.Arg313Gln (c.938G>A) is classified Conflicting classifications of pathogenicity in MAP2K2 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-01-18). AlphaMissense: likely benign (0.1498); Very rare (popmax 0.00659%, sas); Associated with Noonan syndrome and Noonan-related syndrome.

What condition is associated with MAP2K2 p.Arg313Gln (c.938G>A)?

MAP2K2 p.Arg313Gln (c.938G>A) is associated with Noonan syndrome and Noonan-related syndrome, cardiofaciocutaneous syndrome 4, Noonan syndrome (ClinVar).

How common is MAP2K2 p.Arg313Gln (c.938G>A) in the general population?

MAP2K2 p.Arg313Gln (c.938G>A) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about MAP2K2 p.Arg313Gln (c.938G>A)?

AlphaMissense predicts likely benign (score 0.1498) — an in-silico prediction, not a clinical call.

MAP2K2 p.Arg313Gln

c.938G>A · rs151133017 · VCV40839

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.1498 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Noonan syndrome and Noonan-related syndrome

Computational evidence

Protein change
AlphaMissense	0.1498	likely benign
REVEL	0.646	pathogenic-leaning
SaProt	LLR -5.79	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.63, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,766 bp · p 0.55 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00659% South Asian · 6/91,084 alleles

Filtering AF 0.0035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00318%

Overall 0.00403% 65/1,613,068 alleles · very rare exomes 60/1,460,954 · genomes 5/152,114 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,181
Remaining individualsnot grpmax-eligible	0.0064%	15,617
European (non-Finnish)	0.00449%	22,262
African / African-American	0.00267%	37,443

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.Arg313Gln
Coding: c.938G>A
MANE Select: NM_030662
dbSNP: rs151133017
Type: single nucleotide variant
Location: chr19:4097325 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 313: the protein kinase domain

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: cardiofaciocutaneous syndrome 4 Noonan syndrome RASopathy

Similar variants

MAP2K2 p.Arg313Trp Uncertain significance ★★ ⚠ same residue
MAP2K2 p.Arg313= Likely benign ★ same residue
MAP2K2 p.Glu207Lys Likely pathogenic ★★★ same condition
MAP2K2 p.Phe57Cys Pathogenic ★★★ same condition
MAP2K2 p.Phe57Val Pathogenic ★★★ same condition
MAP2K2 p.Pro128Gln Pathogenic ★★★ same condition
MAP2K2 p.Tyr134Cys Likely pathogenic ★★★ same condition
MAP2K2 p.Tyr134His 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/map2k2-p-arg313gln (accessed [today's date]).

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