Is MAP3K7 p.Arg265Cys (c.793C>T) pathogenic?

MAP3K7 p.Arg265Cys (c.793C>T) is classified Uncertain significance in MAP3K7 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.8399); Very rare (popmax 0.00446%, eas); Associated with frontometaphyseal dysplasia 2.

What condition is associated with MAP3K7 p.Arg265Cys (c.793C>T)?

MAP3K7 p.Arg265Cys (c.793C>T) is associated with frontometaphyseal dysplasia 2, cardiospondylocarpofacial syndrome (ClinVar).

How common is MAP3K7 p.Arg265Cys (c.793C>T) in the general population?

MAP3K7 p.Arg265Cys (c.793C>T) is very rare (popmax 0.00446%, eas) (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.Arg265Cys (c.793C>T)?

AlphaMissense predicts likely pathogenic (score 0.8399) — an in-silico prediction, not a clinical call.

MAP3K7 p.Arg265Cys

c.793C>T · VCV3382947

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8399 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

frontometaphyseal dysplasia 2

Computational evidence

Protein change
AlphaMissense	0.8399	likely pathogenic
REVEL	0.807	moderately pathogenic-leaning
SaProt	LLR -10.29	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 9.6	GERP 2.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 33 kb · p 0.12 · regional, not allelic
Overall
CADD	34.0	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

Grpmax group 0.00446% East Asian · 2/44,858 alleles

Filtering AF 0.00315% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00279%

Overall 0.00322% 52/1,612,790 alleles · very rare exomes 50/1,460,714 · genomes 2/152,076 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,429
European (non-Finnish)	0.00407%	24,566
Remaining individualsnot grpmax-eligible	0.0016%	62,410
South Asian	0.0011%	90,990

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.Arg265Cys
Coding: c.793C>T
MANE Select: NM_145331
Type: single nucleotide variant
Location: chr6:90552123 (GRCh38)
Gene constraint: LOEUF 0.397 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.27 · 25 PDB
Residue 265: 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

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.Arg265Gly Uncertain significance ★ ⚠ same residue
MAP3K7 p.Arg265His 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

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-arg265cys (accessed [today's date]).

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