Is FUCA1 p.Trp145Arg (c.433T>C) pathogenic?

FUCA1 p.Trp145Arg (c.433T>C) is classified Conflicting classifications of pathogenicity in FUCA1 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-06-01). AlphaMissense: likely pathogenic (0.9781); Rare (popmax 0.18%, nfe); Associated with fucosidosis.

What condition is associated with FUCA1 p.Trp145Arg (c.433T>C)?

FUCA1 p.Trp145Arg (c.433T>C) is associated with fucosidosis, intellectual disability (ClinVar).

How common is FUCA1 p.Trp145Arg (c.433T>C) in the general population?

FUCA1 p.Trp145Arg (c.433T>C) is rare (popmax 0.18%, nfe) (gnomAD).

How is Fucosidosis inherited?

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

What do computational predictors say about FUCA1 p.Trp145Arg (c.433T>C)?

AlphaMissense predicts likely pathogenic (score 0.9781) — an in-silico prediction, not a clinical call.

FUCA1 p.Trp145Arg

c.433T>C · rs150062050 · VCV296890

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.9781 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.18%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

fucosidosis

Computational evidence

Protein change
AlphaMissense	0.9781	likely pathogenic · top 4% in FUCA1
REVEL	0.803	moderately pathogenic-leaning
SaProt	LLR -16.06	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 23 kb · p 0.31 · regional, not allelic
Overall
CADD	29.0	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 0.18% European (non-Finnish) · 2,124/1,180,030 alleles

Filtering AF 0.174% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.171%

Overall 0.152% 2,449/1,614,226 alleles · rare exomes 2,255/1,461,886 · genomes 194/152,340 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.18%	556
Remaining individualsnot grpmax-eligible	0.152%	658
South Asian	0.142%	706
Middle Eastern	0.132%	758
Admixed American	0.0933%	1,072
African / African-American	0.0373%	2,681
Ashkenazi Jewishnot grpmax-eligible	0.0236%	4,229
Finnishnot grpmax-eligible	0.00312%	32,018

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.Trp145Arg
Coding: c.433T>C
MANE Select: NM_000147
dbSNP: rs150062050
Type: single nucleotide variant
Location: chr1:23865582 (GRCh38)
Gene constraint: LOEUF 1.162 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.60 · 2 PDB
Residue 145: a β-strand

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

Also linked: intellectual disability

For Fucosidosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

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
FUCA1 p.Glu318Ter Pathogenic/Likely pathogenic ★★ same condition
FUCA1 p.Glu353Ter Pathogenic ★★ same condition
FUCA1 p.Glu380Ter 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-trp145arg (accessed [today's date]).

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