Is SUMF1 p.Ala3Val (c.8C>T) pathogenic?

SUMF1 p.Ala3Val (c.8C>T) is classified Uncertain significance in SUMF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-06). AlphaMissense: ambiguous (0.3972); Very rare (popmax 0.00111%, sas); Associated with mucosulfatidosis.

What condition is associated with SUMF1 p.Ala3Val (c.8C>T)?

SUMF1 p.Ala3Val (c.8C>T) is associated with mucosulfatidosis (ClinVar).

How common is SUMF1 p.Ala3Val (c.8C>T) in the general population?

SUMF1 p.Ala3Val (c.8C>T) is very rare (popmax 0.00111%, sas) (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.Ala3Val (c.8C>T)?

AlphaMissense predicts ambiguous (score 0.3972) — an in-silico prediction, not a clinical call.

SUMF1 p.Ala3Val

c.8C>T · rs996881272 · VCV1389858

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3972 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Conditions

mucosulfatidosis

Computational evidence

Protein change
AlphaMissense	0.3972	ambiguous
REVEL	0.494	indeterminate
SaProt	LLR -7.08	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 105 kb · p 0.0001 · regional, not allelic
Overall
CADD	26.5	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 0.00111% South Asian · 1/89,962 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000497% 8/1,608,630 alleles · very rare exomes 8/1,456,302 · genomes 0/152,328 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	62,198
South Asiangrpmax	0.00111%	89,962
European (non-Finnish)	0.000509%	196,336

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala3Val
Coding: c.8C>T
MANE Select: NM_182760
dbSNP: rs996881272
Type: single nucleotide variant
Location: chr3:4467238 (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.Ala3= Likely benign ★ same residue
SUMF1 p.Ala3fs Likely 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-ala3val (accessed [today's date]).

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