Is MAP3K20 p.Pro251Arg (c.752C>G) pathogenic?

MAP3K20 p.Pro251Arg (c.752C>G) is classified Uncertain significance in MAP3K20 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-07). AlphaMissense: likely pathogenic (0.8375); Ultra-rare (popmax 0.0433%, amr).

How common is MAP3K20 p.Pro251Arg (c.752C>G) in the general population?

MAP3K20 p.Pro251Arg (c.752C>G) is ultra-rare (popmax 0.0433%, amr) (gnomAD).

What do computational predictors say about MAP3K20 p.Pro251Arg (c.752C>G)?

AlphaMissense predicts likely pathogenic (score 0.8375) — an in-silico prediction, not a clinical call.

MAP3K20 p.Pro251Arg

c.752C>G · rs1376835331 · VCV2201302

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8375 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0433%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8375	likely pathogenic
REVEL	0.73	pathogenic-leaning
SaProt	LLR -13.69	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 2.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 23 kb · p 0.75 · regional, not allelic
Overall
CADD	27.0	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 0.0433% Admixed American · 25/57,772 alleles

Filtering AF 0.03% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0257%

Overall 0.00187% 30/1,604,658 alleles · ultra-rare exomes 11/1,452,468 · genomes 19/152,190 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0433%	2,311
Remaining individualsnot grpmax-eligible	0.00644%	15,535
African / African-American	0.00134%	74,460

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.Pro251Arg
Coding: c.752C>G
MANE Select: NM_016653
dbSNP: rs1376835331
Type: single nucleotide variant
Location: chr2:173209736 (GRCh38)
Gene constraint: LOEUF 0.569 · pLI 0.14 (gnomAD)
Structure: AlphaFold pLDDT 69.15 · 8 PDB
Residue 251: the protein kinase domain; a UniProt-annotated variant site (in cnm6; decrease of protein abundance)

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

Similar variants

MAP3K20 p.Arg250Trp Uncertain significance ★★ ⚠ same type
MAP3K20 p.Arg293Lys Uncertain significance ★★ same type
MAP3K20 p.Arg536Lys Uncertain significance ★★ ⚠ same type
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
MAP3K20 p.Glu405Gly 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/map3k20-p-pro251arg (accessed [today's date]).

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