Is MAP3K7 p.Met388Val (c.1162A>G) pathogenic?

MAP3K7 p.Met388Val (c.1162A>G) is classified Uncertain significance in MAP3K7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-20). AlphaMissense: likely benign (0.107); Absent from gnomAD v4.1; Associated with frontometaphyseal dysplasia 2.

What condition is associated with MAP3K7 p.Met388Val (c.1162A>G)?

MAP3K7 p.Met388Val (c.1162A>G) is associated with frontometaphyseal dysplasia 2, cardiospondylocarpofacial syndrome (ClinVar).

How common is MAP3K7 p.Met388Val (c.1162A>G) in the general population?

MAP3K7 p.Met388Val (c.1162A>G) is absent from gnomAD v4.1 (gnomAD).

How is Frontometaphyseal dysplasia inherited?

Typically Autosomal dominant, X-linked dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MAP3K7 p.Met388Val (c.1162A>G)?

AlphaMissense predicts likely benign (score 0.107) — an in-silico prediction, not a clinical call.

MAP3K7 p.Met388Val

c.1162A>G · VCV4279825

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.107 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

frontometaphyseal dysplasia 2

Computational evidence

Protein change
AlphaMissense	0.107	likely benign
REVEL	0.328	indeterminate
SaProt	LLR -6.31	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.67	donor gain · deltas
Pangolin	Δ0.42	gain · loss 0.27 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 33 kb · p 0.12 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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.Met388Val
Coding: c.1162A>G
MANE Select: NM_145331
Type: single nucleotide variant
Location: chr6:90547306 (GRCh38)
Gene constraint: LOEUF 0.397 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.27 · 25 PDB
Residue 388: the 'disordered' region

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

Disease context

frontometaphyseal dysplasia 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiospondylocarpofacial syndrome

For Frontometaphyseal dysplasia (Orphanet):

Inheritance: Autosomal dominant, X-linked dominant
Onset: Neonatal

Similar variants

MAP3K7 p.Met388Thr Uncertain significance ★ same residue
MAP3K7 p.Pro512Leu Pathogenic ★★ same condition
MAP3K7 p.Gly451Ser Uncertain significance ★★ ⚠ same condition
MAP3K7 p.Gly110Asp Pathogenic ★ same condition
MAP3K7 p.Gly110Cys Likely pathogenic ★ same condition
MAP3K7 p.Gly168Arg Pathogenic ★ same condition
MAP3K7 p.Ser192Asn Likely pathogenic ★ same condition
MAP3K7 p.Ser272Tyr Likely pathogenic ★ ⚠ 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-met388val (accessed [today's date]).

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