# NM_000199.5(SGSH):c.993C>T (p.Pro331=)

https://sugi.bio/variant/sgsh-p-pro331

## Summary

**SGSH p.Pro331= (c.993C>T)** is classified **Likely benign** in SGSH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-28). Ultra-rare (popmax 0.0658%, mid); Associated with mucopolysaccharidosis type 3A.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs934982826 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0658%, mid)

## For patients & families {#patients}

This is a change in the SGSH gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to mucopolysaccharidosis type 3A.

*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) | Childhood |
| Prevalence | 1-9 / 1 000 000 (Brazil) |
| Clinical trials | 13 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | SGSH is a diagnostic-grade gene on 13 Genomics England panels |

**Commonly reported features of Mucopolysaccharidosis type 3** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Chronic otitis media — Very frequent (99-80%)
- Delayed speech and language development — Very frequent (99-80%)
- Malabsorption — Very frequent (99-80%)
- Coarse hair — Very frequent (99-80%)
- Generalized hirsutism — Very frequent (99-80%)
- Progressive neurologic deterioration — Very frequent (99-80%)
- Sleep abnormality — Very frequent (99-80%)
- Urinary glycosaminoglycan excretion — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007071/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SGSH](https://sugi.bio/atlas/gene/SGSH/) |
| Protein change (HGVS p.) | p.Pro331= |
| Coding change (HGVS c.) | c.993C>T |
| MANE Select transcript | [NM_000199](https://www.ncbi.nlm.nih.gov/nuccore/NM_000199) |
| dbSNP | [rs934982826](https://www.ncbi.nlm.nih.gov/snp/rs934982826/) |
| Variant type | single nucleotide variant |
| Location | chr17:80210968-80210968 (GRCh38) |
| ClinVar | [VCV737032](https://www.ncbi.nlm.nih.gov/clinvar/variation/737032/) |

**All HGVS expressions:** `LRG_1330:g.45977G>A`, `NC_000017.10:g.78184767G>A`, `NC_000017.11:g.80210968G>A`, `NG_008229.1:g.14433C>T`, `NG_032778.1:g.45977G>A`, `NM_000199.5:c.993C>T`, `NM_001352921.3:c.*80C>T`, `NM_001352922.2:c.*43C>T`, `NR_148201.2:n.907C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.21) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 1.922, GERP 0.157, phastCons 1 — weakly conserved position
- CADD: **PHRED 12.85**. 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 deltas (raw): acceptor loss **0.13**, donor loss **0.00**, acceptor gain **0.21**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.13**, donor loss **0.00**, acceptor gain **0.21**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0658%** (mid) · FAF95 0.0224% · FAF99 0.0135% · 4/6,078 in the highest group · 21/1,600,922 alleles overall — ultra-rare (popmax 0.0658%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0658% | 1,520 |
| Remaining individuals (not grpmax-eligible) | 0.00481% | 20,797 |
| South Asian | 0.00329% | 30,359 |
| African / African-American | 0.00267% | 37,468 |
| European (non-Finnish) | 0.000763% | 131,096 |

*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}

**SGSH** population constraint: LOEUF 1.26, pLI 1.0282e-16, missense-Z 0.58086. *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):

- **mucopolysaccharidosis type 3A** — Definitive (AR)

## Protein context {#protein}

Residue **331** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 96.64, 96% of residues very-high.

**2 experimental structure(s)** (PDB): [4MHX](https://www.rcsb.org/structure/4MHX), [4MIV](https://www.rcsb.org/structure/4MIV).

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

*Describes the biological roles of SGSH (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:** SGSH's established molecular role includes N-sulfoglucosamine sulfohydrolase activity. In Reactome, SGSH is annotated in disease pathway(s) including **MPS IIIA - Sanfilippo syndrome A**.

**Disease mechanism (Reactome):** SGSH loss or alteration is curated in [MPS IIIA - Sanfilippo syndrome A](https://reactome.org/content/detail/R-HSA-2206307).

### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [MPS IIIA - Sanfilippo syndrome A](https://reactome.org/content/detail/R-HSA-2206307) | curated |
| [HS-GAG degradation](https://reactome.org/content/detail/R-HSA-2024096) | curated |

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

**Molecular function:** N-sulfoglucosamine sulfohydrolase activity.

**Biological process:** glycosaminoglycan catabolic process, heparan sulfate proteoglycan catabolic process.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-07-28.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2022–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-28 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-01-05 |

## Associated conditions {#conditions}

[mucopolysaccharidosis type 3A](https://sugi.bio/atlas/disease/mucopolysaccharidosis-type-3a/).

**Reported phenotype names (ClinVar):** Mucopolysaccharidosis, MPS-III-A, not specified, AllHighlyPenetrant, SANFILIPPO SYNDROME A, SULFAMIDASE DEFICIENCY, Mucopolysaccharidosis type IIIA (Sanfilippo A), HEPARAN SULFATE SULFATASE DEFICIENCY, Mucopolysaccharidosis, type IIIA, MPS III A, mucopolysaccharidosis type 3A.

## Similar variants {#similar}

Related SGSH variant pages (same residue, condition, or type): [SGSH c.250-2A>G](/variant/sgsh-c-250-minus-2a-g), [SGSH c.356-1G>A](/variant/sgsh-c-356-minus-1g-a), [SGSH c.356-2A>G](/variant/sgsh-c-356-minus-2a-g), [SGSH c.506+1G>A](/variant/sgsh-c-506-plus-1g-a), [SGSH c.745+1G>C](/variant/sgsh-c-745-plus-1g-c), [SGSH c.89-2A>G](/variant/sgsh-c-89-minus-2a-g), [SGSH c.949+1G>A](/variant/sgsh-c-949-plus-1g-a), [SGSH p.Ala63Asp](/variant/sgsh-p-ala63asp).

### 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 737032). 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.*