# NM_002382.5(MAX):c.73C>T (p.Arg25Trp)

https://sugi.bio/variant/max-p-arg25trp

## Summary

**MAX p.Arg25Trp (c.73C>T)** is classified **Conflicting classifications of pathogenicity** in MAX (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-11-09). AlphaMissense: likely pathogenic (0.9995); No allele count reported in gnomAD v4.1 (AN 1,580,300); Associated with hereditary neoplastic syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs2139886995 · 3 submitters · 2 linked conditions · AlphaMissense likely pathogenic · no allele count reported in gnomAD v4.1 (AN 1,580,300)

## For patients & families {#patients}

This is a change in the MAX gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to hereditary neoplastic syndrome.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Clinical trials | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MAX](https://sugi.bio/atlas/gene/MAX/) |
| Protein change (HGVS p.) | p.Arg25Trp |
| Coding change (HGVS c.) | c.73C>T |
| MANE Select transcript | [NM_002382](https://www.ncbi.nlm.nih.gov/nuccore/NM_002382) |
| dbSNP | [rs2139886995](https://www.ncbi.nlm.nih.gov/snp/rs2139886995/) |
| Variant type | single nucleotide variant |
| Location | chr14:65093806-65093806 (GRCh38) |
| ClinVar | [VCV1703285](https://www.ncbi.nlm.nih.gov/clinvar/variation/1703285/) |

**All HGVS expressions:** `LRG_530:g.13704C>T`, `LRG_530t1:c.73C>T`, `NC_000014.8:g.65560524G>A`, `NC_000014.9:g.65093806G>A`, `NG_029830.1:g.13704C>T`, `NM_001271068.2:c.46C>T`, `NM_001271069.2:c.46C>T`, `NM_001320415.2:c.-202C>T`, `NM_001407094.1:c.73C>T`, `NM_001407095.1:c.46C>T`, `NM_001407096.1:c.73C>T`, `NM_001407097.1:c.73C>T`, `NM_001407099.1:c.46C>T`, `NM_001407100.1:c.46C>T`, `NM_001407101.1:c.46C>T`, `NM_001407102.1:c.46C>T`, `NM_001407103.1:c.73C>T`, `NM_001407104.1:c.73C>T`, `NM_001407105.1:c.-202C>T`, `NM_001407106.1:c.-202C>T`, `NM_001407107.1:c.-202C>T`, `NM_001407108.1:c.46C>T`, `NM_001407109.1:c.46C>T`, `NM_001407110.1:c.46C>T`, `NM_001407111.1:c.-295C>T`, `NM_001407112.1:c.-295C>T`, `NM_001407113.1:c.46C>T`, `NM_001407114.1:c.96C>T`, `NM_002382.5:c.73C>T`, `NM_145112.3:c.46C>T`, `NM_145113.3:c.73C>T`, `NM_145114.3:c.73C>T`, `NM_197957.4:c.73C>T`, `NR_045122.1:n.390G>A`, `NR_073137.2:n.197C>T`, `NR_073138.2:n.19C>T`, `NR_176275.1:n.215C>T`, `NR_176276.1:n.215C>T`, `NR_176277.1:n.188C>T`, `NR_176278.1:n.46C>T`, `NR_176279.1:n.149C>T`, `NR_176280.1:n.215C>T`, `NR_176281.1:n.215C>T`, `NR_176282.1:n.19C>T`, `NR_176283.1:n.46C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.9995)
- REVEL 0.947 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.52 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 8.737, GERP 1.94, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 8%** most-pathogenic-predicted substitutions in MAX (of 956 modeled).
- CADD: **PHRED 34.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.56** across the covering region of the MANE Select transcript (65,093,788–65,102,339), spanning 8,551 bp. Chi-square p 0.0042. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,580,300)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**MAX** population constraint: LOEUF 0.288, pLI 0.99819, missense-Z 1.8678; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **hereditary pheochromocytoma-paraganglioma** — Definitive (AD)

## Protein context {#protein}

Residue **25** lies in the bhlh domain; a UniProt-annotated variant site (in pcc; does not repress myc transcriptional activity); the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 82.07, 55% of residues very-high.

**12 experimental structure(s)** (PDB): [1AN2](https://www.rcsb.org/structure/1AN2), [1HLO](https://www.rcsb.org/structure/1HLO), [1NKP](https://www.rcsb.org/structure/1NKP), [1NLW](https://www.rcsb.org/structure/1NLW), [1R05](https://www.rcsb.org/structure/1R05), [5EYO](https://www.rcsb.org/structure/5EYO).

## What this gene does {#gene-function}

*Describes the biological roles of MAX (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** MAX's established molecular role includes DNA-binding transcription factor activity, RNA polymerase II-specific. p.Arg25Trp falls in the bhlh domain.


### Pathways affected {#pathways}

MAX participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cyclin A:Cdk2-associated events at S phase entry](https://reactome.org/content/detail/R-HSA-69656) | curated |
| [Cyclin E associated events during G1/S transition ](https://reactome.org/content/detail/R-HSA-69202) | curated |
| [Transcription of E2F targets under negative control by DREAM complex](https://reactome.org/content/detail/R-HSA-1362277) | curated |
| [Transcriptional Regulation by E2F6](https://reactome.org/content/detail/R-HSA-8953750) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** DNA-binding transcription factor activity, RNA polymerase II-specific, DNA-binding transcription repressor activity, RNA polymerase II-specific, DNA binding, identical protein binding, E-box binding, DNA-binding transcription factor binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, regulation of transcription by RNA polymerase II, positive regulation of DNA-templated transcription.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-11-09.

**Submitter consensus:** conflicting (2 Likely pathogenic, 1 Uncertain significance).

**Submission history:** 3 submissions (2022–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-02-25 |
| Ambry Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-11-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-02-21 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [hereditary pheochromocytoma-paraganglioma](https://sugi.bio/atlas/disease/hereditary-pheochromocytoma-paraganglioma/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, not provided, Hereditary pheochromocytoma and paraganglioma, Neoplastic Syndromes, Hereditary, Tumor predisposition, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome, Hereditary pheochromocytoma-paraganglioma, Hereditary paragangliomas and pheochromocytomas, Hereditary Paraganglioma-Pheochromocytoma Syndromes.

## Similar variants {#similar}

Related MAX variant pages (same residue, condition, or type): [MAX p.Arg25=](/variant/max-p-arg25), [MAX c.295+1G>A](/variant/max-c-295-plus-1g-a), [MAX c.295+1G>T](/variant/max-c-295-plus-1g-t), [MAX p.Ala67Asp](/variant/max-p-ala67asp), [MAX p.Arg33Ter](/variant/max-p-arg33ter), [MAX p.Arg75Ter](/variant/max-p-arg75ter), [MAX p.Gln19Ter](/variant/max-p-gln19ter), [MAX p.Gln91Ter](/variant/max-p-gln91ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1703285). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*