MAX

Chr 14AD

MYC associated transcriptional regulator X

Also known as: MEN5, PDMCS, bHLHd4

NCBI Gene: 4149 ENSG00000125952 UniProt: P61244 OMIM: 154950

MAX encodes a basic helix-loop-helix leucine zipper transcription factor that forms heterodimers with MYC and MAD proteins to regulate gene expression by binding to E-box DNA sequences. Mutations cause autosomal dominant pheochromocytoma susceptibility and polydactyly-macrocephaly syndrome. The gene is highly constrained against loss-of-function variants (pLI 0.83, LOEUF 0.46), reflecting its essential role in transcriptional regulation.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a member of the basic helix-loop-helix leucine zipper (bHLHZ) family of transcription factors. It is able to form homodimers and heterodimers with other family members, which include Mad, Mxi1 and Myc. Myc is an oncoprotein implicated in cell proliferation, differentiation and apoptosis. The homodimers and heterodimers compete for a common DNA target site (the E box) and rearrangement among these dimer forms provides a complex system of transcriptional regulation. Mutations of this gene have been reported to be associated with hereditary pheochromocytoma. A pseudogene of this gene is located on the long arm of chromosome 7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Multiple endocrine neoplasia, type VMIM #621678

Polydactyly-macrocephaly syndromeMIM #620712

UniProtPheochromocytoma

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · hereditary pheochromocytoma-paraganglioma · AD · ClinGen 2021

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

11758

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.46

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — MAX

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.46LOEUF

pLI 0.834

Z-score 2.68

OE 0.10 (0.03–0.46)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.81Z-score

OE missense 0.48 (0.37–0.61)

45 obs / 94.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.10 (0.03–0.46)

0≤0.351.4

Missense OE?0.48 (0.37–0.61)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 1 / 10.3Missense obs/exp: 45 / 94.6Syn Z: 0.56

Background carrier burden — how many people carry a rare variant somewhere in MAX?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 200

380 rare PASS variants

Rare truncating (LoF)

1 in 4,000

52 rare PASS variants

Rare synonymous (reference)

1 in 440

118 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MAX. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 210	1 in 3,800
South Asian	~43k	1 in 130	1 in 4,700
Remaining (unassigned)	~30k	1 in 140	≈ 1 in 15,000
European (Finnish)	~27k	1 in 320	≈ 1 in 8,900
Admixed American	~22k	1 in 200	≈ 1 in 7,500
African / African American	~21k	1 in 120	≈ 1 in 5,900
East Asian	~20k	1 in 280	1 in 890
Ashkenazi Jewish	~13k	1 in 1,600	≈ 1 in 5,900
Middle Eastern	~2,884	1 in 160	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 3 of 5 coding exons well covered in gnomAD exomes; exons 2, 3 marginal. Genomes: all 5.? see exons ↓