Is MAP3K1 p.Val579Met (c.1735G>A) pathogenic?

MAP3K1 p.Val579Met (c.1735G>A) is classified Uncertain significance in MAP3K1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-09-17). AlphaMissense: likely benign (0.2243); Very rare (popmax 0.00667%, amr); Associated with MAP3K1-related disorder.

What condition is associated with MAP3K1 p.Val579Met (c.1735G>A)?

MAP3K1 p.Val579Met (c.1735G>A) is associated with MAP3K1-related disorder (ClinVar).

How common is MAP3K1 p.Val579Met (c.1735G>A) in the general population?

MAP3K1 p.Val579Met (c.1735G>A) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about MAP3K1 p.Val579Met (c.1735G>A)?

AlphaMissense predicts likely benign (score 0.2243) — an in-silico prediction, not a clinical call.

MAP3K1 p.Val579Met

c.1735G>A · VCV3355408

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2243 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MAP3K1-related disorder

Computational evidence

Protein change
AlphaMissense	0.2243	likely benign
REVEL	0.126	moderately benign-leaning
SaProt	LLR -6.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 0.85, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.13 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00667% Admixed American · 4/60,004 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000248% 4/1,614,112 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: MAP3K1
Protein: p.Val579Met
Coding: c.1735G>A
MANE Select: NM_005921
Type: single nucleotide variant
Location: chr5:56875080 (GRCh38)
Gene constraint: LOEUF 0.355 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 1 PDB
Residue 579: an α-helix

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

Disease context

MAP3K1-related disorder

Similar variants

MAP3K1 p.Leu189Pro Pathogenic ★ ⚠ same condition
MAP3K1 p.Leu189Val Likely pathogenic ★ ⚠ same condition
MAP3K1 p.Arg1509His Uncertain significance ⚠ same condition
MAP3K1 p.Thr603Ile Uncertain significance ⚠ same condition
MAP3K1 p.Arg790= Likely benign same condition
MAP3K1 p.Thr1400= Likely benign same condition
MAP3K1 p.Arg186Gly Pathogenic/Likely pathogenic ★★ ⚠ same type
MAP3K1 p.Ala594Ser Uncertain significance ★★ ⚠ 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/map3k1-p-val579met (accessed [today's date]).

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