# NM_018063.5(HELLS):c.1293_1296del (p.Arg432fs)

https://sugi.bio/variant/hells-p-arg432fs

## Summary

**HELLS p.Arg432fs (c.1293_1296del)** is classified **Pathogenic** in HELLS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-24). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2493227029 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the HELLS gene that is reported as disease-causing, but on limited review, 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 | [HELLS](https://sugi.bio/atlas/gene/HELLS/) |
| Protein change (HGVS p.) | p.Arg432fs |
| Coding change (HGVS c.) | c.1293_1296del |
| MANE Select transcript | [NM_018063](https://www.ncbi.nlm.nih.gov/nuccore/NM_018063) |
| dbSNP | [rs2493227029](https://www.ncbi.nlm.nih.gov/snp/rs2493227029/) |
| Variant type | Microsatellite |
| Location | chr10:94583021-94583024 (GRCh38) |
| ClinVar | [VCV2091915](https://www.ncbi.nlm.nih.gov/clinvar/variation/2091915/) |

**All HGVS expressions:** `NC_000010.10:g.96342779AAGA[1]`, `NC_000010.11:g.94583022AAGA[1]`, `NG_047057.1:g.42256AAGA[1]`, `NG_047057.2:g.42236AAGA[1]`, `NM_001289067.2:c.1293_1296del`, `NM_001289068.2:c.1245_1248del`, `NM_001289069.2:c.1197_1200del`, `NM_001289070.2:c.1033-5203_1033-5200del`, `NM_001289071.2:c.921_924del`, `NM_001289072.2:c.937-5203_937-5200del`, `NM_001289073.2:c.879_882del`, `NM_001289074.2:c.210_213del`, `NM_001289075.2:c.75_78del`, `NM_018063.5:c.1293_1296del`

## 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 1.463, GERP -3.33, phastCons 1 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.587, pLI 0.62926. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 12 of 22**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — 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}

**HELLS** population constraint: LOEUF 0.587, pLI 0.62926, missense-Z 2.6551. *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):

- **immunodeficiency-centromeric instability-facial anomalies syndrome 4** — Moderate (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 68.76, 20% of residues very-high.

**4 experimental structure(s)** (PDB): [8SKZ](https://www.rcsb.org/structure/8SKZ), [9Z04](https://www.rcsb.org/structure/9Z04), [9Z05](https://www.rcsb.org/structure/9Z05), [9Z06](https://www.rcsb.org/structure/9Z06).

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

*Describes the biological roles of HELLS (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:** HELLS's established molecular role includes chromatin-protein adaptor activity.


### Pathways affected {#pathways}

HELLS participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [TGFBR3 expression](https://reactome.org/content/detail/R-HSA-9839394) | curated |

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

**Molecular function:** chromatin-protein adaptor activity.

**Biological process:** double-strand break repair via homologous recombination.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-10-24.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-10-24 |

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

## Similar variants {#similar}

Related HELLS variant pages (same residue, condition, or type): [HELLS p.Leu801del](/variant/hells-p-leu801del), [HELLS p.Cys571del](/variant/hells-p-cys571del), [HELLS c.1230-10TC[3]](/variant/hells-c-1230-minus-10tc-3).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2091915). 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.*