# NM_001374675.1(HSF4):c.330C>G (p.Arg110=)

https://sugi.bio/variant/hsf4-p-arg110

## Summary

**HSF4 p.Arg110= (c.330C>G)** is classified **Likely benign** in HSF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-08). Very rare (popmax 0.0011%, sas); Associated with cataract 5 multiple types.

**At a glance:** Likely benign · review: Single submitter · rsID rs754881447 · 1 submitter · 1 linked condition · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the HSF4 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to cataract 5 multiple types.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, X-linked recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | HSF4 is a diagnostic-grade gene on 4 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024547/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [HSF4](https://sugi.bio/atlas/gene/HSF4/) |
| Protein change (HGVS p.) | p.Arg110= |
| Coding change (HGVS c.) | c.330C>G |
| MANE Select transcript | [NM_001374675](https://www.ncbi.nlm.nih.gov/nuccore/NM_001374675) |
| dbSNP | [rs754881447](https://www.ncbi.nlm.nih.gov/snp/rs754881447/) |
| Variant type | single nucleotide variant |
| Location | chr16:67165816-67165816 (GRCh38) |
| ClinVar | [VCV1143016](https://www.ncbi.nlm.nih.gov/clinvar/variation/1143016/) |

**All HGVS expressions:** `NC_000016.10:g.67165816C>G`, `NC_000016.9:g.67199719C>G`, `NG_009294.1:g.7432C>G`, `NG_029566.1:g.315C>G`, `NM_001040667.3:c.330C>G`, `NM_001374674.1:c.330C>G`, `NM_001374675.1:c.330C>G`, `NM_001538.4:c.330C>G`

## 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 -8.291, GERP -3.8 — fast-evolving / accelerated position
- CADD: **PHRED 1.037**. 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>T, Δ0.21 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 **0.0011%** (sas) · FAF95 0.000292% · FAF99 0.000211% · 1/91,008 in the highest group · 9/1,454,858 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0011% | 91,008 |
| European (non-Finnish) | 0.000678% | 147,433 |

*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}

**HSF4** population constraint: LOEUF 1.111, pLI 2.9924e-13, missense-Z 0.47294. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **110** lies in a DNA-binding region.

AlphaFold model confidence (whole protein): pLDDT 61.04, 30% of residues very-high.

**2 experimental structure(s)** (PDB): [6J6V](https://www.rcsb.org/structure/6J6V), [6J6W](https://www.rcsb.org/structure/6J6W) — incl. mutant structure 6J6W.

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

*Describes the biological roles of HSF4 (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:** HSF4's established molecular role includes RNA polymerase II cis-regulatory region sequence-specific DNA binding. p.Arg110= falls in a DNA-binding region.


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

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

**Biological process:** negative regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-05-08.

**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 | 2019-05-08 |

## Associated conditions {#conditions}

[cataract 5 multiple types](https://sugi.bio/atlas/disease/cataract-5-multiple-types/).

**Reported phenotype names (ClinVar):** Cataract 5 multiple types, CATARACT, MARNER TYPE, CATARACT 5, LAMELLAR, Lamellar cataract.

## Similar variants {#similar}

Related HSF4 variant pages (same residue, condition, or type): [HSF4 p.Ala432Val](/variant/hsf4-p-ala432val), [HSF4 p.Arg108Ser](/variant/hsf4-p-arg108ser), [HSF4 p.Glu115Gly](/variant/hsf4-p-glu115gly), [HSF4 p.Glu247=](/variant/hsf4-p-glu247), [HSF4 p.Glu3Gly](/variant/hsf4-p-glu3gly), [HSF4 p.Gly13Asp](/variant/hsf4-p-gly13asp), [HSF4 p.Gly399Asp](/variant/hsf4-p-gly399asp), [HSF4 p.His98Leu](/variant/hsf4-p-his98leu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 1143016). 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.*