Is MAP3K6 p.Arg586Cys (c.1756C>T) pathogenic?

MAP3K6 p.Arg586Cys (c.1756C>T) is classified Uncertain significance in MAP3K6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: ambiguous (0.5623); Absent from gnomAD v4.1.

How common is MAP3K6 p.Arg586Cys (c.1756C>T) in the general population?

MAP3K6 p.Arg586Cys (c.1756C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAP3K6 p.Arg586Cys (c.1756C>T)?

AlphaMissense predicts ambiguous (score 0.5623) — an in-silico prediction, not a clinical call.

MAP3K6 p.Arg586Cys

c.1756C>T · VCV4836777

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5623 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5623	ambiguous
REVEL	0.671	pathogenic-leaning
SaProt	LLR -11.49	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 11 kb · p 0.00042 · regional, not allelic
Overall
CADD	33.0	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: MAP3K6
Protein: p.Arg586Cys
Coding: c.1756C>T
MANE Select: NM_004672
Type: single nucleotide variant
Location: chr1:27361233 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.36

Full MAP3K6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP3K6 p.Arg586His Uncertain significance ★ same residue
MAP3K6 c.1256-2A>G Likely benign ★★ same type
MAP3K6 c.2915+9A>T Benign ★★ same type
MAP3K6 p.Ala405= Benign/Likely benign ★★ same type
MAP3K6 p.Arg499Cys Benign ★★ same type
MAP3K6 p.Asn622Lys Benign ★★ same type
MAP3K6 p.Gln1142Arg Benign ★★ same type
MAP3K6 p.Glu248= Likely benign ★★ 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/map3k6-p-arg586cys (accessed [today's date]).

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