# NM_021615.5(CHST6):c.740del (p.Arg247fs)

https://sugi.bio/variant/chst6-p-arg247fs

## Summary

**CHST6 p.Arg247fs (c.740del)** is classified **Likely pathogenic** in CHST6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-18). Associated with macular corneal dystrophy.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the CHST6 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to macular corneal dystrophy.

*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 recessive |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 100 000 (United States) |
| Clinical trials | 7 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CHST6 is a diagnostic-grade gene on 10 Genomics England panels |

**Commonly reported features of Macular corneal dystrophy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Corneal crystals — Very frequent (99-80%)
- Abnormality of metabolism/homeostasis — Very frequent (99-80%)
- Opacification of the corneal stroma — Very frequent (99-80%)
- Punctate opacification of the cornea — Very frequent (99-80%)
- Recurrent corneal erosions — Frequent (79-30%)
- Severely reduced visual acuity — Frequent (79-30%)
- Decreased corneal thickness — Frequent (79-30%)
- Hyperopic astigmatism — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006953/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CHST6](https://sugi.bio/atlas/gene/CHST6/) |
| Protein change (HGVS p.) | p.Arg247fs |
| Coding change (HGVS c.) | c.740del |
| MANE Select transcript | [NM_021615](https://www.ncbi.nlm.nih.gov/nuccore/NM_021615) |
| Variant type | Deletion |
| Location | chr16:75479089-75479089 (GRCh38) |
| ClinVar | [VCV3581253](https://www.ncbi.nlm.nih.gov/clinvar/variation/3581253/) |

**All HGVS expressions:** `LRG_1252:g.21353del`, `LRG_1252t1:c.740del`, `NC_000016.10:g.75479089del`, `NC_000016.9:g.75512987del`, `NG_016442.2:g.21353del`, `NM_021615.5:c.740del`

## 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 -0.045, GERP -4.14, phastCons 0.165 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.71, pLI 0.26408. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (3 of 3)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- 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.

*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}

**CHST6** population constraint: LOEUF 1.71, pLI 0.26408, missense-Z -1.6367; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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):

- **macular corneal dystrophy** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 90.66, 80% of residues very-high.

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

*Describes the biological roles of CHST6 (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:** CHST6's established molecular role includes N-acetylglucosamine 6-O-sulfotransferase activity. In Reactome, CHST6 is annotated in disease pathway(s) including **Defective CHST6 causes MCDC1**.

**Disease mechanism (Reactome):** CHST6 loss or alteration is curated in [Defective CHST6 causes MCDC1](https://reactome.org/content/detail/R-HSA-3656225).

### Pathways affected {#pathways}

CHST6 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective CHST6 causes MCDC1](https://reactome.org/content/detail/R-HSA-3656225) | curated |
| [Keratan sulfate biosynthesis](https://reactome.org/content/detail/R-HSA-2022854) | curated |

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

**Molecular function:** N-acetylglucosamine 6-O-sulfotransferase activity, keratan sulfotransferase activity.

**Biological process:** N-acetylglucosamine metabolic process, sulfur compound metabolic process, keratan sulfate proteoglycan biosynthetic process.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-05-18.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-05-18 |

## Associated conditions {#conditions}

[macular corneal dystrophy](https://sugi.bio/atlas/disease/macular-corneal-dystrophy/).

**Reported phenotype names (ClinVar):** Macular corneal dystrophy, GROENOUW TYPE II CORNEAL DYSTROPHY, Macular corneal dystrophy Type I.

## Similar variants {#similar}

Related CHST6 variant pages (same residue, condition, or type): [CHST6 p.Gln18fs](/variant/chst6-p-gln18fs), [CHST6 p.Gly227fs](/variant/chst6-p-gly227fs), [CHST6 p.Leu276fs](/variant/chst6-p-leu276fs), [CHST6 p.Lys341fs](/variant/chst6-p-lys341fs), [CHST6 p.Val201_Val207del](/variant/chst6-p-val201-val207del), [CHST6 p.Val233fs](/variant/chst6-p-val233fs), [CHST6 p.Arg269fs](/variant/chst6-p-arg269fs), [CHST6 p.Asn328fs](/variant/chst6-p-asn328fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 3581253). 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.*