Is MAP2K3 p.Val81= (c.243G>A) pathogenic?

MAP2K3 p.Val81= (c.243G>A) is classified Likely benign in MAP2K3 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-06-04). Common (popmax 49.9%, amr) — too common for a highly-penetrant pathogenic allele.

MAP2K3 p.Val81=

Q: How common is MAP2K3 p.Val81= (c.243G>A) in the general population?

MAP2K3 p.Val81= (c.243G>A) is common (popmax 49.9%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.243G>A · rs62057672 · VCV768846

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 49.9%, amr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.58	donor gain · deltas
Constraint at this position
Conservation	phyloP 2.6	GERP 1.4, phastCons 1
Overall
CADD	19.35	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 49.9% Admixed American · 29,145/58,386 alleles

Filtering AF 49.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 49.4%

Overall 49.7% 753,032/1,516,676 alleles · common exomes 676,824/1,364,260 · genomes 76,208/152,416 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	50%	2
Finnishnot grpmax-eligible	50%	2
Admixed Americangrpmax	49.9%	2
East Asian	49.9%	2
South Asian	49.9%	2
Ashkenazi Jewishnot grpmax-eligible	49.9%	2
Middle Eastern	49.8%	2
African / African-American	49.7%	2
Remaining individualsnot grpmax-eligible	49.7%	2
European (non-Finnish)	49.6%	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.Val81=
Coding: c.243G>A
MANE Select: NM_145109
dbSNP: rs62057672
Type: single nucleotide variant
Location: chr17:21300622 (GRCh38)
Gene constraint: LOEUF 0.993 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.13
Residue 81: the protein kinase domain

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

Similar variants

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
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-val81 (accessed [today's date]).

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