# NM_000405.5(GM2A):c.24C>T (p.Pro8=)

https://sugi.bio/variant/gm2a-p-pro8

## Summary

**GM2A p.Pro8= (c.24C>T)** is classified **Likely benign** in GM2A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-07). Very rare (popmax 0.00133%, afr); Associated with Tay-Sachs disease AB variant.

**At a glance:** Likely benign · review: Single submitter · rsID rs752323907 · 1 submitter · 1 linked condition · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the GM2A gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Tay-Sachs disease AB variant.

*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) | Infancy |
| Diagnostic panels | GM2A is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of GM2 gangliosidosis, AB variant** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Dystonia — Very frequent (99-80%)
- Hyperreflexia — Very frequent (99-80%)
- Cerebral atrophy — Very frequent (99-80%)
- Neurodegeneration — Very frequent (99-80%)
- Exaggerated startle response — Very frequent (99-80%)
- Developmental regression — Very frequent (99-80%)
- Progressive spastic quadriplegia — Very frequent (99-80%)
- Short stature — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017406/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GM2A](https://sugi.bio/atlas/gene/GM2A/) |
| Protein change (HGVS p.) | p.Pro8= |
| Coding change (HGVS c.) | c.24C>T |
| MANE Select transcript | [NM_000405](https://www.ncbi.nlm.nih.gov/nuccore/NM_000405) |
| dbSNP | [rs752323907](https://www.ncbi.nlm.nih.gov/snp/rs752323907/) |
| Variant type | single nucleotide variant |
| Location | chr5:151253240-151253240 (GRCh38) |
| ClinVar | [VCV1649650](https://www.ncbi.nlm.nih.gov/clinvar/variation/1649650/) |

**All HGVS expressions:** `NC_000005.10:g.151253240C>T`, `NC_000005.9:g.150632801C>T`, `NG_009059.1:g.5189C>T`, `NM_000405.5:c.24C>T`, `NM_001167607.3:c.24C>T`

## 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 0.421, GERP -4.16 — weakly conserved position
- CADD: **PHRED 3.241**. 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** — this absence is genuinely unknown. Where a position sits between the lowest and the highest record the release holds for its gene, an absent score is a result and we state it as one; this position falls outside them, or the gene has no scored position at all, so that test did not reach here. It may lie outside the scored MANE transcript scope, or it may have been scored with all four deltas below Δ0.2 just past the last surviving record. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00133%** (afr) · FAF95 2.8e-05% · FAF99 1.1e-05% · 1/74,946 in the highest group · 3/1,613,978 alleles overall — very rare (popmax 0.00133%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00133% | 74,946 |
| European (non-Finnish) | 0.000169% | 589,988 |

*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}

**GM2A** population constraint: LOEUF 0.968, pLI 0.11867, missense-Z 0.18945. *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 AB variant** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 89.10, 72% of residues very-high.

**8 experimental structure(s)** (PDB): [1G13](https://www.rcsb.org/structure/1G13), [1PU5](https://www.rcsb.org/structure/1PU5), [1PUB](https://www.rcsb.org/structure/1PUB), [1TJJ](https://www.rcsb.org/structure/1TJJ), [2AF9](https://www.rcsb.org/structure/2AF9), [2AG2](https://www.rcsb.org/structure/2AG2) — incl. mutant structure 2AG9.

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

*Describes the biological roles of GM2A (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.*


### Pathways affected {#pathways}

GM2A participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Glycosphingolipid catabolism](https://reactome.org/content/detail/R-HSA-9840310) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-07-07.

**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 | 2023-07-07 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Tay-Sachs disease, variant AB, Gm2-gangliosidosis, ab variant, GM2 Activator Deficiency.

## Similar variants {#similar}

Related GM2A variant pages (same residue, condition, or type): [GM2A c.*356C>A](/variant/gm2a-c-star-356c-a), [GM2A c.*724G>C](/variant/gm2a-c-star-724g-c), [GM2A p.Ala188Gly](/variant/gm2a-p-ala188gly), [GM2A p.Arg169His](/variant/gm2a-p-arg169his), [GM2A p.Arg169Ser](/variant/gm2a-p-arg169ser), [GM2A p.Arg180His](/variant/gm2a-p-arg180his), [GM2A p.Arg180Ser](/variant/gm2a-p-arg180ser), [GM2A p.Asp116His](/variant/gm2a-p-asp116his).

### 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 1649650). 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.*