# NM_018063.5(HELLS):c.1035T>C (p.His345=)

https://sugi.bio/variant/hells-p-his345

## Summary

**HELLS p.His345= (c.1035T>C)** is classified **Conflicting classifications of pathogenicity** in HELLS (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-05-23). Very rare (popmax 0.00696%, afr); Associated with immunodeficiency-centromeric instability-facial anomalies syndrome 4.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs773771433 · 2 submitters · 1 linked condition · very rare (popmax 0.00696%, afr)

## For patients & families {#patients}

This is a change in the HELLS gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to immunodeficiency-centromeric instability-facial anomalies syndrome 4.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016169/index) · [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.His345= |
| Coding change (HGVS c.) | c.1035T>C |
| MANE Select transcript | [NM_018063](https://www.ncbi.nlm.nih.gov/nuccore/NM_018063) |
| dbSNP | [rs773771433](https://www.ncbi.nlm.nih.gov/snp/rs773771433/) |
| Variant type | single nucleotide variant |
| Location | chr10:94581328-94581328 (GRCh38) |
| ClinVar | [VCV2969713](https://www.ncbi.nlm.nih.gov/clinvar/variation/2969713/) |

**All HGVS expressions:** `NC_000010.10:g.96341085T>C`, `NC_000010.11:g.94581328T>C`, `NG_047057.1:g.40562T>C`, `NG_047057.2:g.40542T>C`, `NM_001289067.2:c.1035T>C`, `NM_001289068.2:c.987T>C`, `NM_001289069.2:c.939T>C`, `NM_001289070.2:c.1032+4523T>C`, `NM_001289071.2:c.663T>C`, `NM_001289072.2:c.936+4619T>C`, `NM_001289073.2:c.621T>C`, `NM_001289074.2:c.-49T>C`, `NM_001289075.2:c.12-1635T>C`, `NM_018063.5:c.1035T>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 2.889, GERP 1.85, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 13.05**. 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 (T>G, Δ0.32 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 **0.00696%** (afr) · FAF95 0.00273% · FAF99 0.00178% · 5/71,788 in the highest group · 5/1,527,164 alleles overall — very rare (popmax 0.00696%, afr).

*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 **345** lies in the helicase atp-binding domain.

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.His345= falls in the helicase atp-binding domain.


### 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-05-23.

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

**Submission history:** 2 submissions (2024–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-01-20 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Uncertain Significance | criteria provided, single submitter | clinical testing | 2025-05-23 |

## Associated conditions {#conditions}

[immunodeficiency-centromeric instability-facial anomalies syndrome 4](https://sugi.bio/atlas/disease/immunodeficiency-centromeric-instability-facial-anomalies-syndrome-4/).

**Reported phenotype names (ClinVar):** Immunodeficiency-centromeric instability-facial anomalies syndrome 4, not provided, none provided.

## Similar variants {#similar}

Related HELLS variant pages (same residue, condition, or type): [HELLS c.370+2T>A](/variant/hells-c-370-plus-2t-a), [HELLS p.Arg513Gly](/variant/hells-p-arg513gly), [HELLS p.Leu420Val](/variant/hells-p-leu420val), [HELLS c.153+10G>T](/variant/hells-c-153-plus-10g-t), [HELLS c.31+20T>C](/variant/hells-c-31-plus-20t-c), [HELLS c.706-18A>G](/variant/hells-c-706-minus-18a-g), [HELLS p.Gln90=](/variant/hells-p-gln90), [HELLS p.Glu655=](/variant/hells-p-glu655).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2969713). 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.*