Is MAP2K3 p.Arg72Leu (c.215G>T) pathogenic?

MAP2K3 p.Arg72Leu (c.215G>T) is classified Uncertain significance in MAP2K3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-24). AlphaMissense: likely pathogenic (0.9409); No allele count reported in gnomAD v4.1 (AN 1,613,138).

How common is MAP2K3 p.Arg72Leu (c.215G>T) in the general population?

MAP2K3 p.Arg72Leu (c.215G>T) is no allele count reported in gnomAD v4.1 (AN 1,613,138) (gnomAD).

What do computational predictors say about MAP2K3 p.Arg72Leu (c.215G>T)?

AlphaMissense predicts likely pathogenic (score 0.9409) — an in-silico prediction, not a clinical call.

MAP2K3 p.Arg72Leu

c.215G>T · VCV4549349

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9409 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,613,138)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9409	likely pathogenic
REVEL	0.813	moderately pathogenic-leaning
SaProt	LLR -15.29	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 12	GERP 2.6, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 20 kb · p 0.26 · regional, not allelic
Overall
CADD	29.9	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

No allele count reported in gnomAD v4.1 (AN 1,613,138). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: MAP2K3
Protein: p.Arg72Leu
Coding: c.215G>T
MANE Select: NM_145109
Type: single nucleotide variant
Location: chr17:21300594 (GRCh38)
Gene constraint: LOEUF 0.993 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.13
Residue 72: the protein kinase domain; a binding site

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

Similar variants

MAP2K3 p.Arg72= Likely benign ★ same residue
MAP2K3 p.Leu215Trp Uncertain significance ★★ ⚠ same type
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

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-arg72leu (accessed [today's date]).

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