Is FUCA1 p.Pro146= (c.438G>A) pathogenic?

FUCA1 p.Pro146= (c.438G>A) is classified Likely benign in FUCA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-23). Ultra-rare (popmax 0.0329%, sas); Associated with fucosidosis.

What condition is associated with FUCA1 p.Pro146= (c.438G>A)?

FUCA1 p.Pro146= (c.438G>A) is associated with fucosidosis (ClinVar).

How common is FUCA1 p.Pro146= (c.438G>A) in the general population?

FUCA1 p.Pro146= (c.438G>A) is ultra-rare (popmax 0.0329%, sas) (gnomAD).

How is Fucosidosis inherited?

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

FUCA1 p.Pro146=

c.438G>A · rs766878135 · VCV1573695

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, sas)

Conditions

fucosidosis

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 -7.7	GERP -4.9
Overall
CADD	1.957	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% South Asian · 30/91,092 alleles

Filtering AF 0.0237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0205%

Overall 0.00551% 89/1,614,096 alleles · ultra-rare exomes 85/1,461,882 · genomes 4/152,214 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0329%	3,036
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	0.00466%	21,455
African / African-American	0.00133%	74,930

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: FUCA1
Protein: p.Pro146=
Coding: c.438G>A
MANE Select: NM_000147
dbSNP: rs766878135
Type: single nucleotide variant
Location: chr1:23865577 (GRCh38)
Gene constraint: LOEUF 1.162 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.60 · 2 PDB
Residue 146: a UniProt-annotated variant site (in)

Full FUCA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

fucosidosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Fucosidosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

FUCA1 p.Pro146Leu Benign/Likely benign ★★ same residue
FUCA1 p.Pro146Arg Uncertain significance ★ ⚠ same residue
FUCA1 p.Pro146fs Pathogenic same residue
FUCA1 c.768+1G>A Pathogenic/Likely pathogenic ★★ same condition
FUCA1 c.768+1G>T Likely pathogenic ★★ same condition
FUCA1 p.Arg264Ter Pathogenic ★★ same condition
FUCA1 p.Gln427Ter Pathogenic ★★ same condition
FUCA1 p.Gln82Ter 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/fuca1-p-pro146 (accessed [today's date]).

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