Is MAP2K1 p.Pro15Arg (c.44C>G) pathogenic?

MAP2K1 p.Pro15Arg (c.44C>G) is classified Uncertain significance in MAP2K1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-27). AlphaMissense: likely benign (0.147); Absent from gnomAD v4.1; Associated with cardiofaciocutaneous syndrome 3.

What condition is associated with MAP2K1 p.Pro15Arg (c.44C>G)?

MAP2K1 p.Pro15Arg (c.44C>G) is associated with cardiofaciocutaneous syndrome 3, RASopathy (ClinVar).

How common is MAP2K1 p.Pro15Arg (c.44C>G) in the general population?

MAP2K1 p.Pro15Arg (c.44C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAP2K1 p.Pro15Arg (c.44C>G)?

AlphaMissense predicts likely benign (score 0.147) — an in-silico prediction, not a clinical call.

MAP2K1 p.Pro15Arg

c.44C>G · VCV3699787

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.147 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

cardiofaciocutaneous syndrome 3

Computational evidence

Protein change
AlphaMissense	0.147	likely benign
REVEL	0.498	indeterminate
SaProt	LLR -8.53	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 1.3, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 66 bp · p 0.84 · regional, not allelic
Overall
CADD	23.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MAP2K1
Protein: p.Pro15Arg
Coding: c.44C>G
MANE Select: NM_002755
Type: single nucleotide variant
Location: chr15:66387391 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI 0.97 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 84.05 · 99 PDB
Residue 15: the 'disordered' region

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

Also linked: RASopathy

Similar variants

MAP2K1 p.Pro15Ala Uncertain significance ★★ ⚠ same residue
MAP2K1 p.Pro15Ser Uncertain significance ★ ⚠ same residue
MAP2K1 p.Pro15= 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

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-pro15arg (accessed [today's date]).

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