Is MAP3K6 p.Arg186Gln (c.557G>A) pathogenic?

MAP3K6 p.Arg186Gln (c.557G>A) is classified Uncertain significance in MAP3K6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-02). AlphaMissense: likely benign (0.0778); Ultra-rare (popmax 0.0164%, mid).

How common is MAP3K6 p.Arg186Gln (c.557G>A) in the general population?

MAP3K6 p.Arg186Gln (c.557G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about MAP3K6 p.Arg186Gln (c.557G>A)?

AlphaMissense predicts likely benign (score 0.0778) — an in-silico prediction, not a clinical call.

MAP3K6 p.Arg186Gln

c.557G>A · VCV4549493

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0778 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0778	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -3.85	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 4	GERP 0.52, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 11 kb · p 0.00042 · regional, not allelic
Overall
CADD	24.6	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00538% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00498%

Overall 0.00527% 85/1,614,000 alleles · ultra-rare exomes 79/1,461,774 · genomes 6/152,226 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
European (non-Finnish)	0.00661%	15,129
African / African-American	0.004%	24,975
Remaining individualsnot grpmax-eligible	0.0032%	31,245
South Asian	0.0011%	91,096

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.Arg186Gln
Coding: c.557G>A
MANE Select: NM_004672
Type: single nucleotide variant
Location: chr1:27364342 (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.Arg186Trp 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-arg186gln (accessed [today's date]).

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