Is MAP3K2 p.Asp375Asn (c.1123G>A) pathogenic?

MAP3K2 p.Asp375Asn (c.1123G>A) is classified Uncertain significance in MAP3K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-11). AlphaMissense: likely pathogenic (0.9433); Very rare (popmax 0.000254%, nfe).

How common is MAP3K2 p.Asp375Asn (c.1123G>A) in the general population?

MAP3K2 p.Asp375Asn (c.1123G>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about MAP3K2 p.Asp375Asn (c.1123G>A)?

AlphaMissense predicts likely pathogenic (score 0.9433) — an in-silico prediction, not a clinical call.

MAP3K2 p.Asp375Asn

c.1123G>A · rs765352195 · VCV2512566

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9433 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9433	likely pathogenic
REVEL	0.248	benign-leaning
SaProt	LLR -12.29	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 25 kb · p 0.016 · regional, not allelic
Overall
CADD	26.0	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 0.000254% European (non-Finnish) · 3/1,179,250 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,612,206 alleles · very rare exomes 2/1,460,064 · genomes 1/152,142 · joint denominator

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: MAP3K2
Protein: p.Asp375Asn
Coding: c.1123G>A
MANE Select: NM_001371910
dbSNP: rs765352195
Type: single nucleotide variant
Location: chr2:127318240 (GRCh38)
Gene constraint: LOEUF 0.6 · pLI 0.79 (gnomAD)
Structure: AlphaFold pLDDT 68.27 · 9 PDB
Residue 375: the protein kinase domain

Full MAP3K2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP3K2 p.Thr293= Benign ★★ same type
MAP3K2 p.Tyr422= Benign ★★ same type
MAP3K2 p.Ala178Val Uncertain significance ★ ⚠ same type
MAP3K2 p.Ala487Thr Uncertain significance ★ ⚠ same type
MAP3K2 p.Ala607Thr Uncertain significance ★ ⚠ same type
MAP3K2 p.Arg151Trp Uncertain significance ★ ⚠ same type
MAP3K2 p.Arg286Ile Uncertain significance ★ ⚠ same type
MAP3K2 p.Arg328Lys Uncertain significance ★ ⚠ 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/map3k2-p-asp375asn (accessed [today's date]).

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