# NM_000520.6(HEXA):c.9C>T (p.Ser3=)

https://sugi.bio/variant/hexa-p-ser3

## Summary

**HEXA p.Ser3= (c.9C>T)** is classified **Benign/Likely benign** in HEXA (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-04). Common (popmax 13.6%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Tay-Sachs disease.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs1800428 · 13 submitters · 1 linked condition · common (popmax 13.6%, eas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the HEXA gene that is classified as benign/likely benign — not considered disease-causing, submitted by 13 submitters, and is linked to Tay-Sachs disease.

*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 | 1-5 / 10 000 (Specific population) |
| Clinical trials | 18 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | HEXA is a diagnostic-grade gene on 20 Genomics England panels |

**Commonly reported features of Tay-Sachs disease** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Muscle weakness — Very frequent (99-80%)
- Progressive spasticity — Very frequent (99-80%)
- Skeletal muscle atrophy — Very frequent (99-80%)
- GM2-ganglioside accumulation — Very frequent (99-80%)
- Abnormality of glycolipid metabolism — Very frequent (99-80%)
- Abnormal enzyme/coenzyme activity — Very frequent (99-80%)
- Visual impairment — Frequent (79-30%)
- Atypical behavior — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007737/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [HEXA](https://sugi.bio/atlas/gene/HEXA/) |
| Protein change (HGVS p.) | p.Ser3= |
| Coding change (HGVS c.) | c.9C>T |
| MANE Select transcript | [NM_000520](https://www.ncbi.nlm.nih.gov/nuccore/NM_000520) |
| dbSNP | [rs1800428](https://www.ncbi.nlm.nih.gov/snp/rs1800428/) |
| Variant type | single nucleotide variant |
| Location | chr15:72375964-72375964 (GRCh38) |
| ClinVar | [VCV93193](https://www.ncbi.nlm.nih.gov/clinvar/variation/93193/) |

**All HGVS expressions:** `NC_000015.10:g.72375964G>A`, `NC_000015.9:g.72668305G>A`, `NG_009017.2:g.5216C>T`, `NM_000520.6:c.9C>T`, `NM_001318825.2:c.9C>T`, `NR_134869.3:n.51C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 13.6%, eas) — too common for a highly-penetrant pathogenic allele.

- **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 1.715, GERP 0.54, phastCons 0.006 — weakly conserved position
- CADD: **PHRED 10.36**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **13.6%** (eas) · FAF95 13.4% · FAF99 13.2% · 6,119/44,864 in the highest group · 68,358/1,613,708 alleles overall — common (popmax 13.6%, eas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 13.6% | 7 |
| Amish (not grpmax-eligible) | 11.1% | 9 |
| South Asian | 4.69% | 21 |
| European (non-Finnish) | 4.33% | 23 |
| Middle Eastern | 4.03% | 25 |
| Remaining individuals (not grpmax-eligible) | 3.93% | 25 |
| Admixed American | 2.6% | 38 |
| Finnish (not grpmax-eligible) | 2.36% | 42 |
| Ashkenazi Jewish (not grpmax-eligible) | 1.73% | 58 |
| African / African-American | 0.711% | 141 |

*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}

**HEXA** population constraint: LOEUF 0.947, pLI 5.5652e-11, missense-Z 0.45674. *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):

- **Tay-Sachs disease** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 93.62, 89% of residues very-high.

**2 experimental structure(s)** (PDB): [2GJX](https://www.rcsb.org/structure/2GJX), [2GK1](https://www.rcsb.org/structure/2GK1).

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

*Describes the biological roles of HEXA (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:** HEXA's established molecular role includes beta-N-acetylhexosaminidase activity. In Reactome, HEXA is annotated in disease pathway(s) including **Defective HEXA causes GM2G1 (Hyaluronan metabolism)**.

**Disease mechanism (Reactome):** HEXA loss or alteration is curated in [Defective HEXA causes GM2G1 (Hyaluronan metabolism)](https://reactome.org/content/detail/R-HSA-3656234).

### Pathways affected {#pathways}

HEXA participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective HEXA causes GM2G1 (Hyaluronan metabolism)](https://reactome.org/content/detail/R-HSA-3656234) | curated |
| [CS/DS degradation](https://reactome.org/content/detail/R-HSA-2024101) | curated |
| [Glycosphingolipid catabolism](https://reactome.org/content/detail/R-HSA-9840310) | curated |
| [Hyaluronan degradation](https://reactome.org/content/detail/R-HSA-2160916) | curated |
| [Keratan sulfate degradation](https://reactome.org/content/detail/R-HSA-2022857) | curated |

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

**Molecular function:** beta-N-acetylhexosaminidase activity, acetylglucosaminyltransferase activity, protein heterodimerization activity.

**Biological process:** glycosaminoglycan biosynthetic process, ganglioside catabolic process, glycosaminoglycan metabolic process.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (10 Benign, 3 Likely benign).

**Submission history:** 13 submissions (2012–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Benign | no assertion criteria provided | clinical testing | 2019-05-20 |
| Genetic Services Laboratory, University of Chicago | Likely benign | no assertion criteria provided | clinical testing |  |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2012-08-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-07-15 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | no assertion criteria provided | clinical testing | 2015-12-16 |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Benign | no assertion criteria provided | clinical testing |  |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2021-07-19 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-06-10 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-27 |

## Associated conditions {#conditions}

[Tay-Sachs disease](https://sugi.bio/atlas/disease/tay-sachs-disease/).

**Reported phenotype names (ClinVar):** Tay-Sachs disease, not specified, not provided, none provided, AllHighlyPenetrant, GM2 gangliosidosis, type 1, Hexosaminidase alpha-subunit deficiency (variant B), Sphingolipidosis, Tay-Sachs, HEXA Disorders, Hexosaminidase A Deficiency.

## Similar variants {#similar}

Related HEXA variant pages (same residue, condition, or type): [HEXA p.Ser3Gly](/variant/hexa-p-ser3gly), [HEXA p.Ser3Ile](/variant/hexa-p-ser3ile), [HEXA p.Ser3Thr](/variant/hexa-p-ser3thr), [HEXA c.1073+1G>A](/variant/hexa-c-1073-plus-1g-a), [HEXA c.1330+1G>A](/variant/hexa-c-1330-plus-1g-a), [HEXA c.1330+2T>C](/variant/hexa-c-1330-plus-2t-c), [HEXA c.1421+1G>C](/variant/hexa-c-1421-plus-1g-c), [HEXA c.1421+1G>T](/variant/hexa-c-1421-plus-1g-t).

### 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 93193). 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.*