# NM_018063.5(HELLS):c.385del (p.Arg129fs)

https://sugi.bio/variant/hells-p-arg129fs

## Summary

**HELLS p.Arg129fs (c.385del)** is classified **Pathogenic** in HELLS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-06). Very rare (popmax 0.00117%, sas).

**At a glance:** Pathogenic · review: Single submitter · rsID rs757191914 · 1 submitter · very rare (popmax 0.00117%, sas)

## 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.Arg129fs |
| Coding change (HGVS c.) | c.385del |
| MANE Select transcript | [NM_018063](https://www.ncbi.nlm.nih.gov/nuccore/NM_018063) |
| dbSNP | [rs757191914](https://www.ncbi.nlm.nih.gov/snp/rs757191914/) |
| Variant type | Deletion |
| Location | chr10:94562820-94562820 (GRCh38) |
| ClinVar | [VCV943584](https://www.ncbi.nlm.nih.gov/clinvar/variation/943584/) |

**All HGVS expressions:** `NC_000010.10:g.96322583del`, `NC_000010.11:g.94562826del`, `NG_047057.1:g.22060del`, `NM_001289067.2:c.385del`, `NM_001289068.2:c.337del`, `NM_001289069.2:c.385del`, `NM_001289070.2:c.385del`, `NM_001289071.2:c.13del`, `NM_001289072.2:c.385del`, `NM_001289073.2:c.21+99del`, `NM_001289074.2:c.-618del`, `NM_001289075.2:c.-637del`, `NM_018063.5:c.385del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 2.632, GERP -1.68, phastCons 0.974 — highly conserved position (PP3-type support)
- 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 6 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 deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00117%** (sas) · FAF95 7e-05% · FAF99 1.9e-05% · 1/85,280 in the highest group · 5/1,562,154 alleles overall — very rare (popmax 0.00117%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00165% | 60,582 |
| South Asian (grpmax) | 0.00117% | 85,280 |
| European (non-Finnish) | 0.000262% | 381,436 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

Residue **129** lies in the 'disordered' region.

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. p.Arg129fs falls in the disordered region.


### 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 2025-06-06.

**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 | 2025-06-06 |

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

## Similar variants {#similar}

Related HELLS variant pages (same residue, condition, or type): [HELLS p.Glu239fs](/variant/hells-p-glu239fs), [HELLS p.Ser164_Ser165insTer](/variant/hells-p-ser164-ser165inster), [HELLS p.Glu157del](/variant/hells-p-glu157del), [HELLS p.Lys156del](/variant/hells-p-lys156del), [HELLS c.1033-5del](/variant/hells-c-1033-minus-5del), [HELLS c.1767+18_1767+23del](/variant/hells-c-1767-plus-18-1767-plus-23del), [HELLS c.1768-6_1768-4del](/variant/hells-c-1768-minus-6-1768-minus-4del), [HELLS c.1851+11del](/variant/hells-c-1851-plus-11del).

### 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 943584). 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.*