Is SUMF1 p.Pro178Ala (c.532C>G) pathogenic?

SUMF1 p.Pro178Ala (c.532C>G) is classified Uncertain significance in SUMF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-15). AlphaMissense: ambiguous (0.408); Ultra-rare (popmax 0.0183%, amr); Associated with mucosulfatidosis.

What condition is associated with SUMF1 p.Pro178Ala (c.532C>G)?

SUMF1 p.Pro178Ala (c.532C>G) is associated with mucosulfatidosis (ClinVar).

How common is SUMF1 p.Pro178Ala (c.532C>G) in the general population?

SUMF1 p.Pro178Ala (c.532C>G) is ultra-rare (popmax 0.0183%, amr) (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.Pro178Ala (c.532C>G)?

AlphaMissense predicts ambiguous (score 0.408) — an in-silico prediction, not a clinical call.

SUMF1 p.Pro178Ala

c.532C>G · rs572034731 · VCV1398335

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.408 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

mucosulfatidosis

Computational evidence

Protein change
AlphaMissense	0.408	ambiguous
REVEL	0.794	moderately pathogenic-leaning
SaProt	LLR -13.13	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 105 kb · p 0.0001 · 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 0.0183% Admixed American · 11/60,004 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.000744% 12/1,613,958 alleles · ultra-rare exomes 5/1,461,782 · genomes 7/152,176 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,455
African / African-American	0.00133%	74,978

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.Pro178Ala
Coding: c.532C>G
MANE Select: NM_182760
dbSNP: rs572034731
Type: single nucleotide variant
Location: chr3:4420134 (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.Pro178= Likely benign ★ same residue
SUMF1 p.Pro178fs 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-pro178ala (accessed [today's date]).

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