Is SGSH p.Ser347Phe (c.1040C>T) pathogenic?

SGSH p.Ser347Phe (c.1040C>T) is classified Conflicting classifications of pathogenicity in SGSH (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-08-15). AlphaMissense: likely pathogenic (0.9374); Ultra-rare (popmax 0.0223%, eas); Associated with mucopolysaccharidosis type 3A.

What condition is associated with SGSH p.Ser347Phe (c.1040C>T)?

SGSH p.Ser347Phe (c.1040C>T) is associated with mucopolysaccharidosis type 3A (ClinVar).

How common is SGSH p.Ser347Phe (c.1040C>T) in the general population?

SGSH p.Ser347Phe (c.1040C>T) is ultra-rare (popmax 0.0223%, eas) (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.Ser347Phe (c.1040C>T)?

AlphaMissense predicts likely pathogenic (score 0.9374) — an in-silico prediction, not a clinical call.

SGSH p.Ser347Phe

c.1040C>T · rs780239925 · VCV556217

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.9374 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mucopolysaccharidosis type 3A

Computational evidence

Protein change
AlphaMissense	0.9374	likely pathogenic
REVEL	0.971	strongly pathogenic-leaning
SaProt	LLR -19.09	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 12	GERP 1.3, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 9,858 bp · p 0.037 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0223% East Asian · 10/44,872 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00917%

Overall 0.000621% 10/1,609,236 alleles · ultra-rare exomes 10/1,456,912 · genomes 0/152,324 · 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.Ser347Phe
Coding: c.1040C>T
MANE Select: NM_000199
dbSNP: rs780239925
Type: single nucleotide variant
Location: chr17:80210921 (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.Ser347= 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-ser347phe (accessed [today's date]).

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