Is SGSH p.Arg19Pro (c.56G>C) pathogenic?

SGSH p.Arg19Pro (c.56G>C) is classified Uncertain significance in SGSH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-04). AlphaMissense: likely benign (0.1024); Very rare (popmax 0.00035%, nfe); Associated with mucopolysaccharidosis type 3A.

What condition is associated with SGSH p.Arg19Pro (c.56G>C)?

SGSH p.Arg19Pro (c.56G>C) is associated with mucopolysaccharidosis type 3A (ClinVar).

How common is SGSH p.Arg19Pro (c.56G>C) in the general population?

SGSH p.Arg19Pro (c.56G>C) is very rare (popmax 0.00035%, nfe) (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.Arg19Pro (c.56G>C)?

AlphaMissense predicts likely benign (score 0.1024) — an in-silico prediction, not a clinical call.

SGSH p.Arg19Pro

c.56G>C · VCV4800923

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1024 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00035%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

mucopolysaccharidosis type 3A

Computational evidence

Protein change
AlphaMissense	0.1024	likely benign
REVEL	0.438	indeterminate
SaProt	LLR -9.12	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.12	GERP 0.12, phastCons 0.001
Regional constraint	o/e 0.92	unconstrained · MANE · 9,858 bp · p 0.037 · regional, not allelic
Overall
CADD	17.66	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00035% European (non-Finnish) · 4/1,141,830 alleles

Filtering AF 8.2e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.5e-05%

Overall 0.000263% 4/1,522,890 alleles · very rare exomes 4/1,370,624 · genomes 0/152,266 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SGSH
Protein: p.Arg19Pro
Coding: c.56G>C
MANE Select: NM_000199
Type: single nucleotide variant
Location: chr17:80220258 (GRCh38)
Gene constraint: LOEUF 1.26 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.64 · 2 PDB

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 p.Arg19= Likely benign ★ same residue
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

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-arg19pro (accessed [today's date]).

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