Is MAP3K7 p.Arg248Pro (c.743G>C) pathogenic?

MAP3K7 p.Arg248Pro (c.743G>C) is classified Uncertain significance in MAP3K7 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-07-06). AlphaMissense: likely pathogenic (0.9994); Absent from gnomAD v4.1.

How common is MAP3K7 p.Arg248Pro (c.743G>C) in the general population?

MAP3K7 p.Arg248Pro (c.743G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAP3K7 p.Arg248Pro (c.743G>C)?

AlphaMissense predicts likely pathogenic (score 0.9994) — an in-silico prediction, not a clinical call.

MAP3K7 p.Arg248Pro

c.743G>C · rs2481817614 · VCV2499378

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9994 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9994	likely pathogenic · top 8% in MAP3K7
REVEL	0.68	pathogenic-leaning
SaProt	LLR -15.54	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.9, phastCons 1
Regional constraint	o/e 0.36	constrained · MANE · 35 kb · p 4.4e-26 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MAP3K7
Protein: p.Arg248Pro
Coding: c.743G>C
MANE Select: NM_145331
dbSNP: rs2481817614
Type: single nucleotide variant
Location: chr6:90552173 (GRCh38)
Gene constraint: LOEUF 0.397 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.27 · 25 PDB
Residue 248: the protein kinase domain; the 'interaction with mapk8ip1' region

Full MAP3K7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP3K7 p.Arg248Gly Uncertain significance ★ ⚠ same residue
MAP3K7 p.Arg248Leu Uncertain significance ★ ⚠ same residue
MAP3K7 p.Arg274Cys Pathogenic/Likely pathogenic ★★ same type
MAP3K7 p.Gly110Ser Pathogenic/Likely pathogenic ★★ same type
MAP3K7 p.Pro512Leu Pathogenic ★★ same type
MAP3K7 p.Ala313Thr Uncertain significance ★★ ⚠ same type
MAP3K7 p.Ala400Thr Uncertain significance ★★ ⚠ same type
MAP3K7 p.Ala6Thr 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/map3k7-p-arg248pro (accessed [today's date]).

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