Is MAP2K2 p.Pro269Leu (c.806C>T) pathogenic?

MAP2K2 p.Pro269Leu (c.806C>T) is classified Uncertain significance in MAP2K2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-17). AlphaMissense: likely benign (0.3236); Rare (popmax 0.112%, eas); Associated with cardiofaciocutaneous syndrome 4.

What condition is associated with MAP2K2 p.Pro269Leu (c.806C>T)?

MAP2K2 p.Pro269Leu (c.806C>T) is associated with cardiofaciocutaneous syndrome 4, RASopathy (ClinVar).

How common is MAP2K2 p.Pro269Leu (c.806C>T) in the general population?

MAP2K2 p.Pro269Leu (c.806C>T) is rare (popmax 0.112%, eas) (gnomAD).

What do computational predictors say about MAP2K2 p.Pro269Leu (c.806C>T)?

AlphaMissense predicts likely benign (score 0.3236) — an in-silico prediction, not a clinical call.

MAP2K2 p.Pro269Leu

c.806C>T · rs368064728 · VCV180906

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.3236 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.112%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cardiofaciocutaneous syndrome 4

Computational evidence

Protein change
AlphaMissense	0.3236	likely benign
REVEL	0.725	pathogenic-leaning
SaProt	LLR -12.63	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,766 bp · p 0.55 · 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 0.112% East Asian · 50/44,614 alleles

Filtering AF 0.0872% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0785%

Overall 0.00479% 77/1,607,542 alleles · rare exomes 75/1,455,320 · genomes 2/152,222 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.112%	892
Middle Eastern	0.0164%	6,080
Remaining individualsnot grpmax-eligible	0.00482%	20,733
South Asian	0.00443%	22,564
European (non-Finnish)	0.00161%	61,969

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.Pro269Leu
Coding: c.806C>T
MANE Select: NM_030662
dbSNP: rs368064728
Type: single nucleotide variant
Location: chr19:4099314 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 269: the protein kinase domain; an α-helix

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: RASopathy

Similar variants

MAP2K2 p.Pro269Arg Uncertain significance ★★★ ⚠ same residue
MAP2K2 p.Pro269Gln Uncertain significance ★★ ⚠ same residue
MAP2K2 p.Pro269= 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

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-pro269leu (accessed [today's date]).

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