Is SUMF1 p.Val281Ile (c.841G>A) pathogenic?

SUMF1 p.Val281Ile (c.841G>A) is classified Uncertain significance in SUMF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-04). AlphaMissense: likely benign (0.1671); Very rare (popmax 0.00483%, nfe); Associated with mucosulfatidosis.

What condition is associated with SUMF1 p.Val281Ile (c.841G>A)?

SUMF1 p.Val281Ile (c.841G>A) is associated with mucosulfatidosis (ClinVar).

How common is SUMF1 p.Val281Ile (c.841G>A) in the general population?

SUMF1 p.Val281Ile (c.841G>A) is very rare (popmax 0.00483%, 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.Val281Ile (c.841G>A)?

AlphaMissense predicts likely benign (score 0.1671) — an in-silico prediction, not a clinical call.

SUMF1 p.Val281Ile

c.841G>A · rs1269294760 · VCV2176301

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1671 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00483%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mucosulfatidosis

Computational evidence

Protein change
AlphaMissense	0.1671	likely benign
REVEL	0.739	pathogenic-leaning
SaProt	LLR -10.34	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 105 kb · p 0.0001 · regional, not allelic
Overall
CADD	31.0	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 0.00483% European (non-Finnish) · 57/1,179,424 alleles

Filtering AF 0.00378% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00345%

Overall 0.00359% 58/1,613,370 alleles · very rare exomes 57/1,461,176 · genomes 1/152,194 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00483%	20,692
Remaining individualsnot grpmax-eligible	0.0016%	62,468

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.Val281Ile
Coding: c.841G>A
MANE Select: NM_182760
dbSNP: rs1269294760
Type: single nucleotide variant
Location: chr3:4410978 (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.Val281= Likely benign ★ 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
SUMF1 c.840+1G>A 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-val281ile (accessed [today's date]).

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