Is MAP3K6 p.Pro869Leu (c.2606C>T) pathogenic?

MAP3K6 p.Pro869Leu (c.2606C>T) is classified Uncertain significance in MAP3K6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-22). AlphaMissense: likely pathogenic (0.9363); Ultra-rare (popmax 0.0151%, amr).

How common is MAP3K6 p.Pro869Leu (c.2606C>T) in the general population?

MAP3K6 p.Pro869Leu (c.2606C>T) is ultra-rare (popmax 0.0151%, amr) (gnomAD).

What do computational predictors say about MAP3K6 p.Pro869Leu (c.2606C>T)?

AlphaMissense predicts likely pathogenic (score 0.9363) — an in-silico prediction, not a clinical call.

MAP3K6 p.Pro869Leu

c.2606C>T · rs762501726 · VCV2234377

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9363 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0151%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9363	likely pathogenic · top 9% in MAP3K6
REVEL	0.576	indeterminate
SaProt	LLR -15.57	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.82, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 11 kb · p 0.00042 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0151% Admixed American · 9/59,782 alleles

Filtering AF 0.00776% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0058%

Overall 0.00236% 38/1,613,398 alleles · ultra-rare exomes 33/1,461,210 · genomes 5/152,188 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0151%	6,642
Remaining individualsnot grpmax-eligible	0.0048%	20,817
European (non-Finnish)	0.00212%	47,193
African / African-American	0.00134%	74,906

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: MAP3K6
Protein: p.Pro869Leu
Coding: c.2606C>T
MANE Select: NM_004672
dbSNP: rs762501726
Type: single nucleotide variant
Location: chr1:27358589 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.36
Residue 869: the protein kinase domain; a UniProt-annotated variant site (in a breast cancer sample; somatic mutation)

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

Similar variants

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
MAP3K6 p.Leu1249= 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-pro869leu (accessed [today's date]).

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