Is MAP2K3 p.Asp135= (c.405C>T) pathogenic?

MAP2K3 p.Asp135= (c.405C>T) is classified Likely benign in MAP2K3 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-06-04). Common (popmax 50%, mid) — too common for a highly-penetrant pathogenic allele.

MAP2K3 p.Asp135=

Q: How common is MAP2K3 p.Asp135= (c.405C>T) in the general population?

MAP2K3 p.Asp135= (c.405C>T) is common (popmax 50%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.405C>T · rs62057721 · VCV768849

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.3	GERP -5.1
Overall
CADD	0.731	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 50% Middle Eastern · 3,029/6,058 alleles

Filtering AF 49.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 49.8%

Overall 50% 803,936/1,608,544 alleles · common exomes 728,075/1,456,702 · genomes 75,861/151,842 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	50%	2
Ashkenazi Jewishnot grpmax-eligible	50%	2
Amishnot grpmax-eligible	50%	2
Middle Easterngrpmax	50%	2
European (non-Finnish)	50%	2
South Asian	50%	2
African / African-American	50%	2
Remaining individualsnot grpmax-eligible	50%	2
East Asian	50%	2
Admixed American	49.5%	2

Finnish 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.Asp135=
Coding: c.405C>T
MANE Select: NM_145109
dbSNP: rs62057721
Type: single nucleotide variant
Location: chr17:21302148 (GRCh38)
Gene constraint: LOEUF 0.993 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.13
Residue 135: 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-asp135 (accessed [today's date]).

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