Is MAP2K2 p.Arg303Leu (c.908G>T) pathogenic?

MAP2K2 p.Arg303Leu (c.908G>T) is classified Uncertain significance in MAP2K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-16). AlphaMissense: ambiguous (0.3646); Very rare (popmax 0.00223%, sas).

How common is MAP2K2 p.Arg303Leu (c.908G>T) in the general population?

MAP2K2 p.Arg303Leu (c.908G>T) is very rare (popmax 0.00223%, sas) (gnomAD).

What do computational predictors say about MAP2K2 p.Arg303Leu (c.908G>T)?

AlphaMissense predicts ambiguous (score 0.3646) — an in-silico prediction, not a clinical call.

MAP2K2 p.Arg303Leu

c.908G>T · rs1251433138 · VCV1328854

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3646 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3646	ambiguous
REVEL	0.729	pathogenic-leaning
SaProt	LLR -7.34	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,766 bp · p 0.55 · regional, not allelic
Overall
CADD	25.5	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 0.00223% South Asian · 2/89,766 alleles

Filtering AF 0.00037% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000138%

Overall 0.000187% 3/1,602,606 alleles · very rare exomes 3/1,450,276 · genomes 0/152,330 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00223%	44,883
European (non-Finnish)	8.51e-05%	1,175,518

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: MAP2K2
Protein: p.Arg303Leu
Coding: c.908G>T
MANE Select: NM_030662
dbSNP: rs1251433138
Type: single nucleotide variant
Location: chr19:4099212 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 303: the protein kinase domain; the 'disordered' region

Full MAP2K2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP2K2 p.Arg303Cys Uncertain significance ★★ ⚠ same residue
MAP2K2 p.Arg303His Uncertain significance ★★ ⚠ same residue
MAP2K2 p.Arg303= Likely benign ★★ same residue
MAP2K2 p.Arg303fs Uncertain significance ★ same residue
MAP2K2 p.Glu207Lys Likely pathogenic ★★★ same type
MAP2K2 p.Phe57Cys Pathogenic ★★★ same type
MAP2K2 p.Phe57Val Pathogenic ★★★ same type
MAP2K2 p.Pro128Gln Pathogenic ★★★ 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/map2k2-p-arg303leu (accessed [today's date]).

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