Is MAP3K7 p.Leu251Arg (c.752T>G) pathogenic?

MAP3K7 p.Leu251Arg (c.752T>G) is classified Uncertain significance in MAP3K7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-10). AlphaMissense: likely pathogenic (0.8574); Very rare (popmax 6.21e-05%); Associated with Inborn genetic diseases.

What condition is associated with MAP3K7 p.Leu251Arg (c.752T>G)?

MAP3K7 p.Leu251Arg (c.752T>G) is associated with Inborn genetic diseases (ClinVar).

How common is MAP3K7 p.Leu251Arg (c.752T>G) in the general population?

MAP3K7 p.Leu251Arg (c.752T>G) is very rare (popmax 6.21e-05%) (gnomAD).

What do computational predictors say about MAP3K7 p.Leu251Arg (c.752T>G)?

AlphaMissense predicts likely pathogenic (score 0.8574) — an in-silico prediction, not a clinical call.

MAP3K7 p.Leu251Arg

c.752T>G · VCV3870267

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8574 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.21e-05%)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8574	likely pathogenic
REVEL	0.941	strongly pathogenic-leaning
SaProt	LLR -8.71	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 33 kb · p 0.12 · regional, not allelic
Overall
CADD	31.0	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 6.21e-05%

Overall 6.21e-05% 1/1,610,432 alleles · very rare exomes 1/1,458,134 · genomes 0/152,298 · 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: MAP3K7
Protein: p.Leu251Arg
Coding: c.752T>G
MANE Select: NM_145331
Type: single nucleotide variant
Location: chr6:90552164 (GRCh38)
Gene constraint: LOEUF 0.397 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.27 · 25 PDB
Residue 251: the protein kinase domain; the 'interaction with mapk8ip1' region; an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAP3K7 p.Ala313Thr Uncertain significance ★★ ⚠ same condition
MAP3K7 p.Ala400Thr Uncertain significance ★★ ⚠ same condition
MAP3K7 p.Ala6Thr Uncertain significance ★★ ⚠ same condition
MAP3K7 p.Arg289Gln Uncertain significance ★★ ⚠ same condition
MAP3K7 p.Arg347His Uncertain significance ★★ ⚠ same condition
MAP3K7 p.Asn342Asp Uncertain significance ★★ ⚠ same condition
MAP3K7 p.Gly411Asp Uncertain significance ★★ ⚠ same condition
MAP3K7 p.Gly451Ser Uncertain significance ★★ ⚠ same condition

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-leu251arg (accessed [today's date]).

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