Is MAP3K1 p.Leu189Pro (c.566T>C) pathogenic?

MAP3K1 p.Leu189Pro (c.566T>C) is classified Pathogenic in MAP3K1 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-05-30). AlphaMissense: likely pathogenic (0.9915); Absent from gnomAD v4.1; Associated with MAP3K1-related disorder.

What condition is associated with MAP3K1 p.Leu189Pro (c.566T>C)?

MAP3K1 p.Leu189Pro (c.566T>C) is associated with MAP3K1-related disorder, 46,XY sex reversal 6 (ClinVar).

How common is MAP3K1 p.Leu189Pro (c.566T>C) in the general population?

MAP3K1 p.Leu189Pro (c.566T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAP3K1 p.Leu189Pro (c.566T>C)?

AlphaMissense predicts likely pathogenic (score 0.9915) — an in-silico prediction, not a clinical call.

MAP3K1 p.Leu189Pro

c.566T>C · rs387906788 · VCV30146

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9915 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

MAP3K1-related disorder

Computational evidence

Protein change
AlphaMissense	0.9915	likely pathogenic ✓ concordant with ClinVar · top 8% in MAP3K1
REVEL	0.524	indeterminate
SaProt	LLR -6.16	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 8,192 bp · p 0.028 · regional, not allelic
Overall
CADD	27.7	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

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: MAP3K1
Protein: p.Leu189Pro
Coding: c.566T>C
MANE Select: NM_005921
dbSNP: rs387906788
Type: single nucleotide variant
Location: chr5:56856683 (GRCh38)
Gene constraint: LOEUF 0.355 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 1 PDB
Residue 189: a UniProt-annotated variant site (in srxy6; increases phosphorylation of the downstream target mapk3/mapk1 compared to wild-type and enhances binding of rhoa to the mutant map3k1 complex); a UniProt-annotated variant site (in srxy6; increases phosphorylation of the downstream targets mapk14 and mapk3/mapk1 compared to wild-type and enhances binding of rhoa to the mutant map3k1 complex)

Full MAP3K1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

MAP3K1-related disorder

Also linked: 46,XY sex reversal 6

Similar variants

MAP3K1 p.Leu189Gln Likely pathogenic ★ ⚠ same residue
MAP3K1 p.Leu189Val Likely pathogenic ★ ⚠ same residue
MAP3K1 p.Leu189Arg Pathogenic ⚠ same residue
MAP3K1 p.Arg186Gly Pathogenic/Likely pathogenic ★★ ⚠ same condition
MAP3K1 p.Ala594Ser Uncertain significance ★★ ⚠ same condition
MAP3K1 p.Arg204Lys Uncertain significance ★★ ⚠ same condition
MAP3K1 p.Gln548Glu Uncertain significance ★★ ⚠ same condition
MAP3K1 c.1035+12C>T Likely benign ★★ 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/map3k1-p-leu189pro (accessed [today's date]).

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