# NM_002382.5(MAX):c.66T>C (p.Ala22=)

https://sugi.bio/variant/max-p-ala22

## Summary

**MAX p.Ala22= (c.66T>C)** is classified **Conflicting classifications of pathogenicity** in MAX (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-02-04). Very rare (popmax 0.000178%, nfe); Associated with hereditary neoplastic syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1566622633 · 2 submitters · 1 linked condition · very rare (popmax 0.000178%, nfe)

## 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 2 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.Ala22= |
| Coding change (HGVS c.) | c.66T>C |
| MANE Select transcript | [NM_002382](https://www.ncbi.nlm.nih.gov/nuccore/NM_002382) |
| dbSNP | [rs1566622633](https://www.ncbi.nlm.nih.gov/snp/rs1566622633/) |
| Variant type | single nucleotide variant |
| Location | chr14:65093813-65093813 (GRCh38) |
| ClinVar | [VCV2587740](https://www.ncbi.nlm.nih.gov/clinvar/variation/2587740/) |

**All HGVS expressions:** `LRG_530:g.13697T>C`, `LRG_530t1:c.66T>C`, `NC_000014.8:g.65560531A>G`, `NC_000014.9:g.65093813A>G`, `NG_029830.1:g.13697T>C`, `NM_001271068.2:c.39T>C`, `NM_001271069.2:c.39T>C`, `NM_001320415.2:c.-209T>C`, `NM_001407094.1:c.66T>C`, `NM_001407095.1:c.39T>C`, `NM_001407096.1:c.66T>C`, `NM_001407097.1:c.66T>C`, `NM_001407098.1:c.63+7733T>C`, `NM_001407099.1:c.39T>C`, `NM_001407100.1:c.39T>C`, `NM_001407101.1:c.39T>C`, `NM_001407102.1:c.39T>C`, `NM_001407103.1:c.66T>C`, `NM_001407104.1:c.66T>C`, `NM_001407105.1:c.-209T>C`, `NM_001407106.1:c.-209T>C`, `NM_001407107.1:c.-209T>C`, `NM_001407108.1:c.39T>C`, `NM_001407109.1:c.39T>C`, `NM_001407110.1:c.39T>C`, `NM_001407111.1:c.-302T>C`, `NM_001407112.1:c.-302T>C`, `NM_001407113.1:c.39T>C`, `NM_001407114.1:c.89T>C`, `NM_002382.4:c.66T>C`, `NM_002382.5:c.66T>C`, `NM_145112.3:c.39T>C`, `NM_145113.3:c.66T>C`, `NM_145114.3:c.66T>C`, `NM_197957.4:c.66T>C`, `NR_045122.1:n.397A>G`, `NR_073137.2:n.190T>C`, `NR_073138.2:n.12T>C`, `NR_176275.1:n.208T>C`, `NR_176276.1:n.208T>C`, `NR_176277.1:n.181T>C`, `NR_176278.1:n.39T>C`, `NR_176279.1:n.142T>C`, `NR_176280.1:n.208T>C`, `NR_176281.1:n.208T>C`, `NR_176282.1:n.12T>C`, `NR_176283.1:n.39T>C`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 6.215, GERP -0.391, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 15.18**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (A>T, Δ0.31 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000178%** (nfe) · FAF95 3e-05% · FAF99 1.1e-05% · 2/1,126,368 in the highest group · 2/1,555,436 alleles overall — very rare (popmax 0.000178%, nfe).

*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 **22** lies in 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.Ala22= falls in the disordered region.


### 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 2025-02-04.

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

**Submission history:** 2 submissions (2023–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-06-17 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-02-04 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, not provided, Tumor predisposition, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome, Neoplastic Syndromes, Hereditary, none provided.

## Similar variants {#similar}

Related MAX variant pages (same residue, condition, or type): [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.Gln91Ter](/variant/max-p-gln91ter), [MAX p.Gln97Ter](/variant/max-p-gln97ter), [MAX c.63+4C>T](/variant/max-c-63-plus-4c-t).

### 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 2587740). 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.*