Is MAP3K20 p.Ile686Val (c.2056A>G) pathogenic?

MAP3K20 p.Ile686Val (c.2056A>G) is classified Uncertain significance in MAP3K20 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-02). AlphaMissense: likely benign (0.0606); Ultra-rare (popmax 0.066%, mid).

How common is MAP3K20 p.Ile686Val (c.2056A>G) in the general population?

MAP3K20 p.Ile686Val (c.2056A>G) is ultra-rare (popmax 0.066%, mid) (gnomAD).

What do computational predictors say about MAP3K20 p.Ile686Val (c.2056A>G)?

AlphaMissense predicts likely benign (score 0.0606) — an in-silico prediction, not a clinical call.

MAP3K20 p.Ile686Val

c.2056A>G · rs565825340 · VCV1439205

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0606 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.066%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0606	likely benign
REVEL	0.074	moderately benign-leaning
SaProt	LLR -5.54	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.3	GERP -1.1, phastCons 0.001
Regional constraint	o/e 0.95	unconstrained · MANE · 28 kb · p 0.29 · regional, not allelic
Overall
CADD	5.364	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 0.066% Middle Eastern · 4/6,062 alleles

Filtering AF 0.0225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.00384% 62/1,614,160 alleles · ultra-rare exomes 55/1,461,874 · genomes 7/152,286 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.066%	1,516
Remaining individualsnot grpmax-eligible	0.0176%	5,682
Admixed American	0.00833%	12,003
European (non-Finnish)	0.00347%	28,781
South Asian	0.0011%	91,076

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: MAP3K20
Protein: p.Ile686Val
Coding: c.2056A>G
MANE Select: NM_016653
dbSNP: rs565825340
Type: single nucleotide variant
Location: chr2:173266403 (GRCh38)
Gene constraint: LOEUF 0.569 · pLI 0.14 (gnomAD)
Structure: AlphaFold pLDDT 69.15 · 8 PDB
Residue 686: a UniProt-annotated variant site (in cnm6; decrease of protein abundance); the 'disordered' region; the 'sensing domain (s)' region

Full MAP3K20 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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MAP3K20 p.Arg634Gly Uncertain significance ★★ ⚠ same type
MAP3K20 p.Arg774Trp Uncertain significance ★★ ⚠ same type
MAP3K20 p.Arg795His Uncertain significance ★★ ⚠ same type
MAP3K20 p.Gln632Ter Uncertain significance ★★ same type
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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/map3k20-p-ile686val (accessed [today's date]).

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