Is MAP2K2 p.Asp271Asn (c.811G>A) pathogenic?

MAP2K2 p.Asp271Asn (c.811G>A) is classified Uncertain significance in MAP2K2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-14). AlphaMissense: likely benign (0.1144); Very rare (popmax 0.00224%, eas); Associated with cardiofaciocutaneous syndrome 4.

What condition is associated with MAP2K2 p.Asp271Asn (c.811G>A)?

MAP2K2 p.Asp271Asn (c.811G>A) is associated with cardiofaciocutaneous syndrome 4, cardiofaciocutaneous syndrome, RASopathy (ClinVar).

How common is MAP2K2 p.Asp271Asn (c.811G>A) in the general population?

MAP2K2 p.Asp271Asn (c.811G>A) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about MAP2K2 p.Asp271Asn (c.811G>A)?

AlphaMissense predicts likely benign (score 0.1144) — an in-silico prediction, not a clinical call.

MAP2K2 p.Asp271Asn

c.811G>A · rs758031424 · VCV666425

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1144 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cardiofaciocutaneous syndrome 4

Computational evidence

Protein change
AlphaMissense	0.1144	likely benign
REVEL	0.277	benign-leaning
SaProt	LLR -6.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.45, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,766 bp · p 0.55 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00224% East Asian · 1/44,602 alleles

Filtering AF 0.000805% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000651%

Overall 0.00124% 20/1,607,054 alleles · very rare exomes 19/1,454,856 · genomes 1/152,198 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,602
Remaining individualsnot grpmax-eligible	0.00161%	62,194
Finnishnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.00136%	73,577
South Asian	0.00111%	90,150

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.Asp271Asn
Coding: c.811G>A
MANE Select: NM_030662
dbSNP: rs758031424
Type: single nucleotide variant
Location: chr19:4099309 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 271: 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: cardiofaciocutaneous syndrome RASopathy

Similar variants

MAP2K2 p.Asp271= Likely benign ★★★ same residue
MAP2K2 p.Asp271Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
MAP2K2 p.Asp271Tyr Uncertain significance ★★ ⚠ 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-asp271asn (accessed [today's date]).

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