Is MAP2K1 p.Arg227Ser (c.681G>T) pathogenic?

MAP2K1 p.Arg227Ser (c.681G>T) is classified Uncertain significance in MAP2K1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-17). AlphaMissense: likely pathogenic (0.9986); Absent from gnomAD v4.1.

How common is MAP2K1 p.Arg227Ser (c.681G>T) in the general population?

MAP2K1 p.Arg227Ser (c.681G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAP2K1 p.Arg227Ser (c.681G>T)?

AlphaMissense predicts likely pathogenic (score 0.9986) — an in-silico prediction, not a clinical call.

MAP2K1 p.Arg227Ser

c.681G>T · rs2140668342 · VCV1677929

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9986 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9986	likely pathogenic
REVEL	0.704	pathogenic-leaning
SaProt	LLR -14.29	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.4	GERP -3.5, phastCons 1
Regional constraint	o/e 0.21	constrained · MANE · 3,228 bp · p 9.9e-09 · regional, not allelic
Overall
CADD	23.4	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.Arg227Ser
Coding: c.681G>T
MANE Select: NM_002755
dbSNP: rs2140668342
Type: single nucleotide variant
Location: chr15:66481867 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI 0.97 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 84.05 · 99 PDB
Residue 227: the protein kinase domain; 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-arg227ser (accessed [today's date]).

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