Is SUMF1 p.Ala2Pro (c.4G>C) pathogenic?

SUMF1 p.Ala2Pro (c.4G>C) is classified Uncertain significance in SUMF1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-03-03). AlphaMissense: likely benign (0.2248); Absent from gnomAD v4.1; Associated with mucosulfatidosis.

What condition is associated with SUMF1 p.Ala2Pro (c.4G>C)?

SUMF1 p.Ala2Pro (c.4G>C) is associated with mucosulfatidosis (ClinVar).

How common is SUMF1 p.Ala2Pro (c.4G>C) in the general population?

SUMF1 p.Ala2Pro (c.4G>C) is absent from gnomAD v4.1 (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.Ala2Pro (c.4G>C)?

AlphaMissense predicts likely benign (score 0.2248) — an in-silico prediction, not a clinical call.

SUMF1 p.Ala2Pro

c.4G>C · VCV4062031

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2248 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

mucosulfatidosis

Computational evidence

Protein change
AlphaMissense	0.2248	likely benign
REVEL	0.513	indeterminate
SaProt	LLR -7.19	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 5.5	GERP 1.6, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 105 kb · p 0.0001 · regional, not allelic
Overall
CADD	25.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SUMF1
Protein: p.Ala2Pro
Coding: c.4G>C
MANE Select: NM_182760
Type: single nucleotide variant
Location: chr3:4467242 (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.Ala2Val Uncertain significance ★ ⚠ same residue
SUMF1 p.Ala2Gly Uncertain significance ⚠ 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-ala2pro (accessed [today's date]).

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