Is MAP2K1 p.Pro323Ser (c.967C>T) pathogenic?

MAP2K1 p.Pro323Ser (c.967C>T) is classified Uncertain significance in MAP2K1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-04). AlphaMissense: likely pathogenic (0.9981); Very rare (popmax 8.48e-05%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with MAP2K1 p.Pro323Ser (c.967C>T)?

MAP2K1 p.Pro323Ser (c.967C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is MAP2K1 p.Pro323Ser (c.967C>T) in the general population?

MAP2K1 p.Pro323Ser (c.967C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about MAP2K1 p.Pro323Ser (c.967C>T)?

AlphaMissense predicts likely pathogenic (score 0.9981) — an in-silico prediction, not a clinical call.

MAP2K1 p.Pro323Ser

c.967C>T · rs1301109791 · VCV1767767

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9981 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9981	likely pathogenic
REVEL	0.817	moderately pathogenic-leaning
SaProt	LLR -12.21	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 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 5,593 bp · p 6.7e-08 · regional, not allelic
Overall
CADD	28.4	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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,916 alleles

Overall 0.000657% 1/152,138 alleles · very rare

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.Pro323Ser
Coding: c.967C>T
MANE Select: NM_002755
dbSNP: rs1301109791
Type: single nucleotide variant
Location: chr15:66489221 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI 0.97 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 84.05 · 99 PDB
Residue 323: the protein kinase domain; an α-helix

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

Disease context

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

Similar variants

MAP2K1 p.Pro323= Likely benign ★ same residue
MAP2K1 p.Ala268Val Uncertain significance ★★ ⚠ same condition
MAP2K1 p.Ala32Val Uncertain significance ★★ ⚠ same condition
MAP2K1 p.Arg108Gln Uncertain significance ★★ ⚠ same condition
MAP2K1 p.Arg291Gly Uncertain significance ★★ ⚠ same condition
MAP2K1 p.Asp217Asn Uncertain significance ★★ ⚠ same condition
MAP2K1 p.Asp267Glu Uncertain significance ★★ ⚠ same condition
MAP2K1 p.Ile107Val Uncertain significance ★★ ⚠ 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-pro323ser (accessed [today's date]).

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