Is MAP2K1 p.Val93Ile (c.277G>A) pathogenic?

MAP2K1 p.Val93Ile (c.277G>A) is classified Conflicting classifications of pathogenicity in MAP2K1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0563); Very rare (popmax 0.00458%, nfe); Associated with melorheostosis.

What condition is associated with MAP2K1 p.Val93Ile (c.277G>A)?

MAP2K1 p.Val93Ile (c.277G>A) is associated with melorheostosis, Noonan syndrome 1, cardiofaciocutaneous syndrome 3 (ClinVar).

How common is MAP2K1 p.Val93Ile (c.277G>A) in the general population?

MAP2K1 p.Val93Ile (c.277G>A) is very rare (popmax 0.00458%, nfe) (gnomAD).

What do computational predictors say about MAP2K1 p.Val93Ile (c.277G>A)?

AlphaMissense predicts likely benign (score 0.0563) — an in-silico prediction, not a clinical call.

MAP2K1 p.Val93Ile

c.277G>A · rs151207265 · VCV180896

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0563 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00458%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

melorheostosis

Computational evidence

Protein change
AlphaMissense	0.0563	likely benign
REVEL	0.222	benign-leaning
SaProt	LLR -6.36	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 9.7	GERP 0.92, phastCons 1
Regional constraint	o/e 0.46	unconstrained · MANE · 94 kb · p 1.7e-15 · regional, not allelic
Overall
CADD	19.74	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 0.00458% European (non-Finnish) · 54/1,179,928 alleles

Filtering AF 0.00358% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00321%

Overall 0.00347% 56/1,613,908 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00458%	21,851
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596
Remaining individualsnot grpmax-eligible	0.0016%	62,478

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.Val93Ile
Coding: c.277G>A
MANE Select: NM_002755
dbSNP: rs151207265
Type: single nucleotide variant
Location: chr15:66435223 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI 0.97 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 84.05 · 99 PDB
Residue 93: the protein kinase domain; a β-strand

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

Disease context

melorheostosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Noonan syndrome 1 cardiofaciocutaneous syndrome 3 RASopathy

Similar variants

MAP2K1 p.Val93= Likely benign ★★ same residue
MAP2K1 p.Arg108Leu Likely pathogenic ★★★ same condition
MAP2K1 p.Asn122Asp Pathogenic ★★★ ⚠ same condition
MAP2K1 p.Asp67Asn Pathogenic ★★★ same condition
MAP2K1 p.Glu203Gly Pathogenic ★★★ same condition
MAP2K1 p.Leu42Arg Likely pathogenic ★★★ same condition
MAP2K1 p.Leu42Phe Pathogenic ★★★ same condition
MAP2K1 p.Leu92Arg 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-val93ile (accessed [today's date]).

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