Is MAP2K2 p.Pro109Leu (c.326C>T) pathogenic?

MAP2K2 p.Pro109Leu (c.326C>T) is classified Conflicting classifications of pathogenicity in MAP2K2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-24). AlphaMissense: likely pathogenic (0.7522); Ultra-rare (popmax 0.0165%, mid); Associated with cardiofaciocutaneous syndrome 4.

What condition is associated with MAP2K2 p.Pro109Leu (c.326C>T)?

MAP2K2 p.Pro109Leu (c.326C>T) is associated with cardiofaciocutaneous syndrome 4, Noonan syndrome 1, RASopathy (ClinVar).

How common is MAP2K2 p.Pro109Leu (c.326C>T) in the general population?

MAP2K2 p.Pro109Leu (c.326C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about MAP2K2 p.Pro109Leu (c.326C>T)?

AlphaMissense predicts likely pathogenic (score 0.7522) — an in-silico prediction, not a clinical call.

MAP2K2 p.Pro109Leu

c.326C>T · rs544242665 · VCV228849

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.7522 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cardiofaciocutaneous syndrome 4

Computational evidence

Protein change
AlphaMissense	0.7522	likely pathogenic
REVEL	0.711	pathogenic-leaning
SaProt	LLR -13.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 18 kb · p 1.4e-08 · regional, not allelic
Overall
CADD	33.0	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 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000992% 16/1,613,436 alleles · ultra-rare exomes 12/1,461,086 · genomes 4/152,350 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
African / African-American	0.00266%	37,533
South Asian	0.0022%	45,543
European (non-Finnish)	0.000932%	107,269

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.Pro109Leu
Coding: c.326C>T
MANE Select: NM_030662
dbSNP: rs544242665
Type: single nucleotide variant
Location: chr19:4110633 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 109: the protein kinase domain

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

Disease context

cardiofaciocutaneous syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Noonan syndrome 1 RASopathy

Similar variants

MAP2K2 p.Pro109Ala Uncertain significance ★★ same residue
MAP2K2 p.Pro109= 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-pro109leu (accessed [today's date]).

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