Is MAP2K2 p.Asp341Tyr (c.1021G>T) pathogenic?

MAP2K2 p.Asp341Tyr (c.1021G>T) is classified Uncertain significance in MAP2K2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-17). AlphaMissense: likely benign (0.2171); Ultra-rare (popmax 0.0334%, mid).

How common is MAP2K2 p.Asp341Tyr (c.1021G>T) in the general population?

MAP2K2 p.Asp341Tyr (c.1021G>T) is ultra-rare (popmax 0.0334%, mid) (gnomAD).

What do computational predictors say about MAP2K2 p.Asp341Tyr (c.1021G>T)?

AlphaMissense predicts likely benign (score 0.2171) — an in-silico prediction, not a clinical call.

MAP2K2 p.Asp341Tyr

c.1021G>T · VCV3906711

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2171 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2171	likely benign
REVEL	0.415	indeterminate
SaProt	LLR -9.17	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; 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 0.64, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,766 bp · p 0.55 · regional, not allelic
Overall
CADD	28.2	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 0.0334% Middle Eastern · 2/5,986 alleles

Filtering AF 0.00589% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00245%

Overall 0.000451% 7/1,551,248 alleles · ultra-rare exomes 5/1,399,004 · genomes 2/152,244 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0334%	2,993
South Asian	0.00119%	84,038
European (non-Finnish)	0.000349%	286,707

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.Asp341Tyr
Coding: c.1021G>T
MANE Select: NM_030662
Type: single nucleotide variant
Location: chr19:4095413 (GRCh38)
Gene constraint: LOEUF 0.858 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.54 · 3 PDB
Residue 341: the protein kinase domain; an α-helix

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

Similar variants

MAP2K2 p.Asp341Ala Uncertain significance ★★ ⚠ same residue
MAP2K2 p.Asp341Asn Uncertain significance ★★ ⚠ same residue
MAP2K2 p.Asp341Val Uncertain significance ★ ⚠ same residue
MAP2K2 p.Asp341= Likely benign ★ 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-asp341tyr (accessed [today's date]).

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