# NM_018063.5(HELLS):c.694G>C (p.Glu232Gln)

https://sugi.bio/variant/hells-p-glu232gln

## Summary

**HELLS p.Glu232Gln (c.694G>C)** is classified **Uncertain significance** in HELLS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: ambiguous (0.5345); Very rare (popmax 8.52e-05%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 8.52e-05%, nfe)

## For patients & families {#patients}

This is a change in the HELLS gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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.Glu232Gln |
| Coding change (HGVS c.) | c.694G>C |
| MANE Select transcript | [NM_018063](https://www.ncbi.nlm.nih.gov/nuccore/NM_018063) |
| Variant type | single nucleotide variant |
| Location | chr10:94574176-94574176 (GRCh38) |
| ClinVar | [VCV4621413](https://www.ncbi.nlm.nih.gov/clinvar/variation/4621413/) |

**All HGVS expressions:** `NC_000010.10:g.96333933G>C`, `NC_000010.11:g.94574176G>C`, `NG_047057.1:g.33410G>C`, `NG_047057.2:g.33390G>C`, `NM_001289067.2:c.694G>C`, `NM_001289068.2:c.646G>C`, `NM_001289069.2:c.694G>C`, `NM_001289070.2:c.694G>C`, `NM_001289071.2:c.322G>C`, `NM_001289072.2:c.694G>C`, `NM_001289073.2:c.280G>C`, `NM_001289074.2:c.-309G>C`, `NM_001289075.2:c.-328G>C`, `NM_018063.5:c.694G>C`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.5345) — no call either way
- REVEL 0.782 (moderately pathogenic-leaning)
- SaProt LLR -8.001 (tolerated)
- → **In-silico consensus:** REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate
- Conservation: phyloP 11.783, GERP 2.32, phastCons 1 — highly conserved
- CADD: **PHRED 28.9**. 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.*
- Regional missense constraint: **o/e 0.30** across the covering region of the MANE Select transcript (94,574,103–94,574,686), spanning 583 bp — the region is depleted of missense variation. Chi-square p 5.4e-11. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.76 donor 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 **8.52e-05%** (nfe) · 1/1,173,074 in the highest group · 1/1,606,454 alleles overall — very rare (popmax 8.52e-05%, 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}

**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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-26.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-26 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related HELLS variant pages (same residue, condition, or type): [HELLS p.Ala16Pro](/variant/hells-p-ala16pro), [HELLS p.Arg319Trp](/variant/hells-p-arg319trp), [HELLS p.Arg507Gln](/variant/hells-p-arg507gln), [HELLS p.Arg541Gln](/variant/hells-p-arg541gln), [HELLS p.Arg5Trp](/variant/hells-p-arg5trp), [HELLS p.Arg66Cys](/variant/hells-p-arg66cys), [HELLS p.Arg721Cys](/variant/hells-p-arg721cys), [HELLS p.Asp117Gly](/variant/hells-p-asp117gly).

### 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 4621413). 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.*