# NM_014862.4(ARNT2):c.1413C>T (p.Ala471=)

https://sugi.bio/variant/arnt2-p-ala471

## Summary

**ARNT2 p.Ala471= (c.1413C>T)** is classified **Likely benign** in ARNT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-21). Very rare (popmax 0.00668%, eas).

**At a glance:** Likely benign · review: Single submitter · rsID rs201074895 · 1 submitter · very rare (popmax 0.00668%, eas)

## For patients & families {#patients}

This is a change in the ARNT2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ARNT2](https://sugi.bio/atlas/gene/ARNT2/) |
| Protein change (HGVS p.) | p.Ala471= |
| Coding change (HGVS c.) | c.1413C>T |
| MANE Select transcript | [NM_014862](https://www.ncbi.nlm.nih.gov/nuccore/NM_014862) |
| dbSNP | [rs201074895](https://www.ncbi.nlm.nih.gov/snp/rs201074895/) |
| Variant type | single nucleotide variant |
| Location | chr15:80575010-80575010 (GRCh38) |
| ClinVar | [VCV2419290](https://www.ncbi.nlm.nih.gov/clinvar/variation/2419290/) |

**All HGVS expressions:** `NC_000015.10:g.80575010C>T`, `NC_000015.9:g.80867351C>T`, `NM_014862.4:c.1413C>T`

## 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 -10.358, GERP -2.32 — fast-evolving / accelerated position
- CADD: **PHRED 0.686**. 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 (C>A, Δ0.35 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 **0.00668%** (eas) · FAF95 0.00215% · FAF99 0.00191% · 3/44,890 in the highest group · 44/1,613,942 alleles overall — very rare (popmax 0.00668%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00668% | 14,963 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,829 |
| European (non-Finnish) | 0.00297% | 33,714 |
| Admixed American | 0.00167% | 59,996 |
| African / African-American | 0.00134% | 74,870 |
| South Asian | 0.0011% | 91,084 |

*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}

**ARNT2** population constraint: LOEUF 0.498, pLI 0.94024, missense-Z 2.3501. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 59.49, 22% of residues very-high.

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

*Describes the biological roles of ARNT2 (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:** ARNT2's established molecular role includes DNA-binding transcription factor activity, RNA polymerase II-specific.


### Pathways affected {#pathways}

ARNT2 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Aryl hydrocarbon receptor signalling](https://reactome.org/content/detail/R-HSA-8937144) | curated |
| [Endogenous sterols](https://reactome.org/content/detail/R-HSA-211976) | curated |
| [PPARA activates gene expression](https://reactome.org/content/detail/R-HSA-1989781) | curated |
| [Phase I - Functionalization of compounds](https://reactome.org/content/detail/R-HSA-211945) | curated |
| [Xenobiotics](https://reactome.org/content/detail/R-HSA-211981) | curated |
| [NPAS4 regulates expression of target genes](https://reactome.org/content/detail/R-HSA-9768919) | electronic |

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

**Molecular function:** DNA-binding transcription factor activity, RNA polymerase II-specific, protein heterodimerization activity, sequence-specific double-stranded DNA binding.

**Biological process:** response to hypoxia, regulation of DNA-templated transcription, brain development, positive regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-05-21.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-05-21 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related ARNT2 variant pages (same residue, condition, or type): [ARNT2 p.Arg159Ter](/variant/arnt2-p-arg159ter), [ARNT2 p.Ala483Val](/variant/arnt2-p-ala483val), [ARNT2 p.Arg262Lys](/variant/arnt2-p-arg262lys), [ARNT2 p.Asp705Tyr](/variant/arnt2-p-asp705tyr), [ARNT2 p.Gln520Arg](/variant/arnt2-p-gln520arg), [ARNT2 p.Gly472Ser](/variant/arnt2-p-gly472ser), [ARNT2 p.Gly546Arg](/variant/arnt2-p-gly546arg), [ARNT2 p.Ile347Phe](/variant/arnt2-p-ile347phe).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 2419290). 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.*