Is MAP2K1 p.Ile379Val (c.1135A>G) pathogenic?

MAP2K1 p.Ile379Val (c.1135A>G) is classified Uncertain significance in MAP2K1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-12). AlphaMissense: likely benign (0.0611); Very rare (popmax 0.00534%, afr); Associated with melorheostosis.

What condition is associated with MAP2K1 p.Ile379Val (c.1135A>G)?

MAP2K1 p.Ile379Val (c.1135A>G) is associated with melorheostosis, cardiofaciocutaneous syndrome 3, RASopathy (ClinVar).

How common is MAP2K1 p.Ile379Val (c.1135A>G) in the general population?

MAP2K1 p.Ile379Val (c.1135A>G) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about MAP2K1 p.Ile379Val (c.1135A>G)?

AlphaMissense predicts likely benign (score 0.0611) — an in-silico prediction, not a clinical call.

MAP2K1 p.Ile379Val

c.1135A>G · rs373794940 · VCV659397

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0611 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

melorheostosis

Computational evidence

Protein change
AlphaMissense	0.0611	likely benign
REVEL	0.328	indeterminate
SaProt	LLR -5.29	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 0.98, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 5,593 bp · p 6.7e-08 · regional, not allelic
Overall
CADD	19.32	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 0.00534% African / African-American · 4/74,926 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00105% 17/1,614,090 alleles · very rare exomes 15/1,461,892 · genomes 2/152,198 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,732
Admixed American	0.005%	20,001
East Asian	0.00223%	44,890
European (non-Finnish)	0.000763%	131,117

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.Ile379Val
Coding: c.1135A>G
MANE Select: NM_002755
dbSNP: rs373794940
Type: single nucleotide variant
Location: chr15:66490568 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI 0.97 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 84.05 · 99 PDB
Residue 379: an α-helix

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: cardiofaciocutaneous syndrome 3 RASopathy

Similar variants

MAP2K1 p.Ile379= 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-ile379val (accessed [today's date]).

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