Is MAP2K1 p.Pro321Ser (c.961C>T) pathogenic?

MAP2K1 p.Pro321Ser (c.961C>T) is classified Conflicting classifications of pathogenicity in MAP2K1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-08-13). AlphaMissense: ambiguous (0.3935); Ultra-rare (popmax 0.04%, amr); Associated with Noonan syndrome 1.

What condition is associated with MAP2K1 p.Pro321Ser (c.961C>T)?

MAP2K1 p.Pro321Ser (c.961C>T) is associated with Noonan syndrome 1, cardiofaciocutaneous syndrome 3, RASopathy (ClinVar).

How common is MAP2K1 p.Pro321Ser (c.961C>T) in the general population?

MAP2K1 p.Pro321Ser (c.961C>T) is ultra-rare (popmax 0.04%, amr) (gnomAD).

What do computational predictors say about MAP2K1 p.Pro321Ser (c.961C>T)?

AlphaMissense predicts ambiguous (score 0.3935) — an in-silico prediction, not a clinical call.

MAP2K1 p.Pro321Ser

c.961C>T · rs771613524 · VCV582017

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.3935 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.04%, amr)

Conditions

Noonan syndrome 1

Computational evidence

Protein change
AlphaMissense	0.3935	ambiguous
REVEL	0.636	indeterminate
SaProt	LLR -8.01	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.1, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 5,593 bp · p 6.7e-08 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.04% Admixed American · 24/60,000 alleles

Filtering AF 0.0276% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0234%

Overall 0.00149% 24/1,613,460 alleles · ultra-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.Pro321Ser
Coding: c.961C>T
MANE Select: NM_002755
dbSNP: rs771613524
Type: single nucleotide variant
Location: chr15:66489215 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI 0.97 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 84.05 · 99 PDB
Residue 321: the protein kinase domain; an α-helix

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

Disease context

Noonan syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiofaciocutaneous syndrome 3 RASopathy

Similar variants

MAP2K1 p.Pro321Arg Uncertain significance ★ ⚠ same residue
MAP2K1 p.Pro321Thr Uncertain significance ★ ⚠ 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

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-pro321ser (accessed [today's date]).

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