Is MAP2K3 p.Arg96Trp (c.286C>T) pathogenic?

MAP2K3 p.Arg96Trp (c.286C>T) is classified Conflicting classifications of pathogenicity in MAP2K3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-02-16). AlphaMissense: likely pathogenic (0.905); Common (popmax 50%, amr) — too common for a highly-penetrant pathogenic allele; Associated with MAP2K3-related disorder.

What condition is associated with MAP2K3 p.Arg96Trp (c.286C>T)?

MAP2K3 p.Arg96Trp (c.286C>T) is associated with MAP2K3-related disorder (ClinVar).

What do computational predictors say about MAP2K3 p.Arg96Trp (c.286C>T)?

AlphaMissense predicts likely pathogenic (score 0.905) — an in-silico prediction, not a clinical call.

MAP2K3 p.Arg96Trp

Q: How common is MAP2K3 p.Arg96Trp (c.286C>T) in the general population?

MAP2K3 p.Arg96Trp (c.286C>T) is common (popmax 50%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.286C>T · VCV3891623

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.905 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 50%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

MAP2K3-related disorder

Computational evidence

Protein change
AlphaMissense	0.905	likely pathogenic
REVEL	0.375	indeterminate
SaProt	LLR -12.98	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 2.4, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 20 kb · p 0.26 · 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

Grpmax group 50% Admixed American · 29,842/59,702 alleles

Filtering AF 49.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 49.7%

Overall 49.9% 771,864/1,548,344 alleles · common exomes 695,652/1,395,920 · genomes 76,212/152,424 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	50%	2
Admixed Americangrpmax	50%	2
Finnishnot grpmax-eligible	50%	2
Middle Eastern	50%	2
East Asian	50%	2
South Asian	49.9%	2
Ashkenazi Jewishnot grpmax-eligible	49.9%	2
African / African-American	49.9%	2
Remaining individualsnot grpmax-eligible	49.9%	2
European (non-Finnish)	49.8%	2

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: MAP2K3
Protein: p.Arg96Trp
Coding: c.286C>T
MANE Select: NM_145109
Type: single nucleotide variant
Location: chr17:21300880 (GRCh38)
Gene constraint: LOEUF 0.993 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.13
Residue 96: the protein kinase domain; a UniProt-annotated variant site (in)

Full MAP2K3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

MAP2K3-related disorder

Similar variants

MAP2K3 p.Leu215Trp Uncertain significance ★★ ⚠ same condition
MAP2K3 c.568+10C>T Benign ★★ same type
MAP2K3 p.Ala220= Benign ★★ same type
MAP2K3 p.Ala225= Likely benign ★★ same type
MAP2K3 p.Leu25= Benign ★★ same type
MAP2K3 p.Leu319= Likely benign ★★ same type
MAP2K3 p.Pro40Thr Benign ★★ same type
MAP2K3 p.Ser286= 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/map2k3-p-arg96trp (accessed [today's date]).

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