Is MAP2K1 p.Ser218Pro (c.652T>C) pathogenic?

MAP2K1 p.Ser218Pro (c.652T>C) is classified Uncertain significance in MAP2K1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-03). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1.

How common is MAP2K1 p.Ser218Pro (c.652T>C) in the general population?

MAP2K1 p.Ser218Pro (c.652T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAP2K1 p.Ser218Pro (c.652T>C)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

MAP2K1 p.Ser218Pro

c.652T>C · rs2140668016 · VCV1677490

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic · top 9% in MAP2K1
REVEL	0.915	moderately pathogenic-leaning
SaProt	LLR -16.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.21	constrained · MANE · 3,228 bp · p 9.9e-09 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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.Ser218Pro
Coding: c.652T>C
MANE Select: NM_002755
dbSNP: rs2140668016
Type: single nucleotide variant
Location: chr15:66481838 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI 0.97 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 84.05 · 99 PDB
Residue 218: the protein kinase domain; a modified residue (phosphoserine; by braf and raf1); an α-helix

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

Similar variants

MAP2K1 p.Arg108Leu Likely pathogenic ★★★ same type
MAP2K1 p.Asn122Asp Pathogenic ★★★ ⚠ same type
MAP2K1 p.Asp67Asn Pathogenic ★★★ same type
MAP2K1 p.Glu203Gly Pathogenic ★★★ same type
MAP2K1 p.Leu42Arg Likely pathogenic ★★★ same type
MAP2K1 p.Leu42Phe Pathogenic ★★★ same type
MAP2K1 p.Leu92Arg Pathogenic ★★★ same type
MAP2K1 p.Lys57Gln Likely pathogenic ★★★ same type

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-ser218pro (accessed [today's date]).

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