Is MAP2K1 p.Val357Ile (c.1069G>A) pathogenic?

MAP2K1 p.Val357Ile (c.1069G>A) is classified Uncertain significance in MAP2K1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-11). AlphaMissense: likely benign (0.0739); Ultra-rare (popmax 0.0111%, eas); Associated with cardiofaciocutaneous syndrome 3.

What condition is associated with MAP2K1 p.Val357Ile (c.1069G>A)?

MAP2K1 p.Val357Ile (c.1069G>A) is associated with cardiofaciocutaneous syndrome 3 (ClinVar).

How common is MAP2K1 p.Val357Ile (c.1069G>A) in the general population?

MAP2K1 p.Val357Ile (c.1069G>A) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about MAP2K1 p.Val357Ile (c.1069G>A)?

AlphaMissense predicts likely benign (score 0.0739) — an in-silico prediction, not a clinical call.

MAP2K1 p.Val357Ile

c.1069G>A · VCV4279718

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0739 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cardiofaciocutaneous syndrome 3

Computational evidence

Protein change
AlphaMissense	0.0739	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -6.99	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 5,593 bp · p 6.7e-08 · regional, not allelic
Overall
CADD	23.7	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 0.0111% East Asian · 5/44,866 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000436% 7/1,607,340 alleles · ultra-rare exomes 5/1,455,178 · genomes 2/152,162 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,973
Remaining individualsnot grpmax-eligible	0.00161%	62,238
European (non-Finnish)	8.52e-05%	1,173,940

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: MAP2K1
Protein: p.Val357Ile
Coding: c.1069G>A
MANE Select: NM_002755
Type: single nucleotide variant
Location: chr15:66490502 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI 0.97 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 84.05 · 99 PDB
Residue 357: the protein kinase domain

Full MAP2K1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cardiofaciocutaneous syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAP2K1 p.Arg108Leu Likely pathogenic ★★★ same condition
MAP2K1 p.Asn122Asp Pathogenic ★★★ ⚠ same condition
MAP2K1 p.Asp67Asn Pathogenic ★★★ same condition
MAP2K1 p.Leu42Phe Pathogenic ★★★ same condition
MAP2K1 p.Lys57Gln Likely pathogenic ★★★ same condition
MAP2K1 p.Phe53Ser Likely pathogenic ★★★ same condition
MAP2K1 p.Pro124Ser Pathogenic ★★★ same condition
MAP2K1 p.Tyr130Cys 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/map2k1-p-val357ile (accessed [today's date]).

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