Is SGSH p.Cys495Ser (c.1484G>C) pathogenic?

SGSH p.Cys495Ser (c.1484G>C) is classified Uncertain significance in SGSH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-02). AlphaMissense: likely pathogenic (0.9506); Absent from gnomAD v4.1; Associated with mucopolysaccharidosis type 3A.

What condition is associated with SGSH p.Cys495Ser (c.1484G>C)?

SGSH p.Cys495Ser (c.1484G>C) is associated with mucopolysaccharidosis type 3A (ClinVar).

How common is SGSH p.Cys495Ser (c.1484G>C) in the general population?

SGSH p.Cys495Ser (c.1484G>C) is absent from gnomAD v4.1 (gnomAD).

How is Mucopolysaccharidosis type 3 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SGSH p.Cys495Ser (c.1484G>C)?

AlphaMissense predicts likely pathogenic (score 0.9506) — an in-silico prediction, not a clinical call.

SGSH p.Cys495Ser

c.1484G>C · rs1598736666 · VCV3161053

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9506 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mucopolysaccharidosis type 3A

Computational evidence

Protein change
AlphaMissense	0.9506	likely pathogenic · top 9% in SGSH
REVEL	0.932	strongly pathogenic-leaning
SaProt	LLR -14.75	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 9,858 bp · p 0.037 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SGSH
Protein: p.Cys495Ser
Coding: c.1484G>C
MANE Select: NM_000199
dbSNP: rs1598736666
Type: single nucleotide variant
Location: chr17:80210477 (GRCh38)
Gene constraint: LOEUF 1.26 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.64 · 2 PDB
Residue 495: a β-strand; a disulfide bond; a UniProt-annotated variant site (in mps3a)

Full SGSH gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mucopolysaccharidosis type 3A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Mucopolysaccharidosis type 3 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Brazil)

Similar variants

SGSH c.250-2A>G Pathogenic/Likely pathogenic ★★ same condition
SGSH c.356-1G>A Pathogenic/Likely pathogenic ★★ same condition
SGSH c.356-2A>G Pathogenic/Likely pathogenic ★★ same condition
SGSH c.506+1G>A Pathogenic/Likely pathogenic ★★ same condition
SGSH c.745+1G>C Pathogenic/Likely pathogenic ★★ same condition
SGSH c.89-2A>G Pathogenic/Likely pathogenic ★★ same condition
SGSH c.949+1G>A Pathogenic/Likely pathogenic ★★ same condition
SGSH p.Ala63Asp Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/sgsh-p-cys495ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown