Is SUMF1 p.Ala221= (c.663A>C) pathogenic?

SUMF1 p.Ala221= (c.663A>C) is classified Likely benign in SUMF1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-13). Ultra-rare (popmax 0.0198%, sas); Associated with mucosulfatidosis.

What condition is associated with SUMF1 p.Ala221= (c.663A>C)?

SUMF1 p.Ala221= (c.663A>C) is associated with mucosulfatidosis (ClinVar).

How common is SUMF1 p.Ala221= (c.663A>C) in the general population?

SUMF1 p.Ala221= (c.663A>C) is ultra-rare (popmax 0.0198%, sas) (gnomAD).

How is Multiple sulfatase deficiency inherited?

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

SUMF1 p.Ala221=

c.663A>C · rs756709971 · VCV1105990

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0198%, sas)

Conditions

mucosulfatidosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -7.4	GERP -5.5
Overall
CADD	1.042	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0198% South Asian · 18/91,084 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00167% 27/1,613,986 alleles · ultra-rare exomes 22/1,461,770 · genomes 5/152,216 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0198%	5,060
Admixed American	0.005%	20,003
Remaining individualsnot grpmax-eligible	0.0016%	62,478
African / African-American	0.00133%	74,936
European (non-Finnish)	0.000339%	295,008

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.Ala221=
Coding: c.663A>C
MANE Select: NM_182760
dbSNP: rs756709971
Type: single nucleotide variant
Location: chr3:4418072 (GRCh38)
Gene constraint: LOEUF 1.254 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.39 · 21 PDB

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 p.Ala221Thr Uncertain significance ★ ⚠ same residue
SUMF1 p.Ala221fs Pathogenic same residue
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

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-ala221 (accessed [today's date]).

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