Is SUMF1 p.Ala366Val (c.1097C>T) pathogenic?

SUMF1 p.Ala366Val (c.1097C>T) is classified Uncertain significance in SUMF1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-01-30). AlphaMissense: likely benign (0.1331); Very rare (popmax 8.47e-05%, nfe); Associated with mucosulfatidosis.

What condition is associated with SUMF1 p.Ala366Val (c.1097C>T)?

SUMF1 p.Ala366Val (c.1097C>T) is associated with mucosulfatidosis (ClinVar).

How common is SUMF1 p.Ala366Val (c.1097C>T) in the general population?

SUMF1 p.Ala366Val (c.1097C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Multiple sulfatase deficiency inherited?

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

What do computational predictors say about SUMF1 p.Ala366Val (c.1097C>T)?

AlphaMissense predicts likely benign (score 0.1331) — an in-silico prediction, not a clinical call.

SUMF1 p.Ala366Val

c.1097C>T · VCV4062034

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1331 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

mucosulfatidosis

Computational evidence

Protein change
AlphaMissense	0.1331	likely benign
REVEL	0.473	indeterminate
SaProt	LLR -7.27	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 9.6	GERP 2, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 105 kb · p 0.0001 · regional, not allelic
Overall
CADD	22.6	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 8.47e-05% European (non-Finnish) · 1/1,179,994 alleles

Overall 6.2e-05% 1/1,614,168 alleles · very rare exomes 1/1,461,816 · genomes 0/152,352 · 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: SUMF1
Protein: p.Ala366Val
Coding: c.1097C>T
MANE Select: NM_182760
Type: single nucleotide variant
Location: chr3:4362172 (GRCh38)
Gene constraint: LOEUF 1.254 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.39 · 21 PDB
Residue 366: a UniProt-annotated variant site (in msd; almost abolished enzyme activity); a β-strand

Full SUMF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mucosulfatidosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Multiple sulfatase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Antenatal, Childhood, Infancy, Neonatal

Similar variants

SUMF1 c.271-1G>C Likely pathogenic ★★ same condition
SUMF1 c.445-1G>A Pathogenic/Likely pathogenic ★★ same condition
SUMF1 c.445-2A>G Pathogenic/Likely pathogenic ★★ same condition
SUMF1 c.520-1G>C Likely pathogenic ★★ same condition
SUMF1 c.602+1G>A Pathogenic/Likely pathogenic ★★ same condition
SUMF1 c.603-1G>C Pathogenic ★★ same condition
SUMF1 c.840+1G>A Likely pathogenic ★★ same condition
SUMF1 c.954+1G>T 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/sumf1-p-ala366val (accessed [today's date]).

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