Is MAP2K1 p.Pro89Thr (c.265C>A) pathogenic?

MAP2K1 p.Pro89Thr (c.265C>A) is classified Likely pathogenic in MAP2K1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-10). AlphaMissense: likely benign (0.1957); Very rare (popmax 8.47e-05%, nfe); Associated with cardiofaciocutaneous syndrome 3.

What condition is associated with MAP2K1 p.Pro89Thr (c.265C>A)?

MAP2K1 p.Pro89Thr (c.265C>A) is associated with cardiofaciocutaneous syndrome 3 (ClinVar).

How common is MAP2K1 p.Pro89Thr (c.265C>A) in the general population?

MAP2K1 p.Pro89Thr (c.265C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about MAP2K1 p.Pro89Thr (c.265C>A)?

AlphaMissense predicts likely benign (score 0.1957) — an in-silico prediction, not a clinical call.

MAP2K1 p.Pro89Thr

c.265C>A · rs1265809314 · VCV1299563

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1957 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

cardiofaciocutaneous syndrome 3

Computational evidence

Protein change
AlphaMissense	0.1957	likely benign ⚠ discordant with ClinVar
REVEL	0.631	indeterminate
SaProt	LLR -10.14	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.46	unconstrained · MANE · 94 kb · p 1.7e-15 · regional, not allelic
Overall
CADD	25.2	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 8.47e-05% European (non-Finnish) · 1/1,180,000 alleles

Overall 6.2e-05% 1/1,614,122 alleles · very rare exomes 1/1,461,858 · genomes 0/152,264 · joint denominator

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.Pro89Thr
Coding: c.265C>A
MANE Select: NM_002755
dbSNP: rs1265809314
Type: single nucleotide variant
Location: chr15:66435211 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI 0.97 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 84.05 · 99 PDB
Residue 89: the protein kinase domain; a turn

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

Similar variants

MAP2K1 p.Pro89Ser 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.Leu42Phe Pathogenic ★★★ same condition
MAP2K1 p.Lys57Gln Likely pathogenic ★★★ same condition
MAP2K1 p.Phe53Ser Likely pathogenic ★★★ same condition
MAP2K1 p.Pro124Ser 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-pro89thr (accessed [today's date]).

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