Is FAT2 p.Pro509= (c.1527C>T) pathogenic?

FAT2 p.Pro509= (c.1527C>T) is classified Benign in FAT2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). Common (popmax 93.3%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with spinocerebellar ataxia 45.

What condition is associated with FAT2 p.Pro509= (c.1527C>T)?

FAT2 p.Pro509= (c.1527C>T) is associated with spinocerebellar ataxia 45 (ClinVar).

How is Spinocerebellar ataxia type 45 inherited?

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

FAT2 p.Pro509=

Q: How common is FAT2 p.Pro509= (c.1527C>T) in the general population?

FAT2 p.Pro509= (c.1527C>T) is common (popmax 93.3%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1527C>T · rs1465690 · VCV1242230

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 93.3%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

spinocerebellar ataxia 45

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.46	GERP -4.4, phastCons 0.88
Overall
CADD	5.239	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 93.3% European (non-Finnish) · 1,101,047/1,179,986 alleles

Filtering AF 93.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 93.1%

Overall 91.5% 1,476,464/1,614,030 alleles · common exomes 1,339,056/1,461,812 · genomes 137,408/152,218 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	93.5%	1
European (non-Finnish)grpmax	93.3%	1
Finnishnot grpmax-eligible	91.7%	1
Amishnot grpmax-eligible	91.2%	1
Middle Eastern	91.2%	1
South Asian	91.1%	1
Remaining individualsnot grpmax-eligible	91%	1
African / African-American	89.9%	1
East Asian	78.1%	1
Admixed American	67.4%	1

Ashkenazi Jewish 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: FAT2
Protein: p.Pro509=
Coding: c.1527C>T
MANE Select: NM_001447
dbSNP: rs1465690
Type: single nucleotide variant
Location: chr5:151567405 (GRCh38)
Gene constraint: LOEUF 0.554 · pLI <0.01 (gnomAD)
Residue 509: the cadherin 4 domain

Full FAT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spinocerebellar ataxia 45 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Spinocerebellar ataxia type 45 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

FAT2 p.Pro509Thr Uncertain significance ★★ ⚠ same residue
FAT2 p.Ala1079Asp Uncertain significance ★★ ⚠ same condition
FAT2 p.Arg3558Gln Uncertain significance ★★ ⚠ same condition
FAT2 p.Gly1261Arg Uncertain significance ★★ ⚠ same condition
FAT2 p.Leu3279Val Uncertain significance ★★ ⚠ same condition
FAT2 p.Lys2586Arg Uncertain significance ★★ ⚠ same condition
FAT2 p.Pro146Ser Uncertain significance ★★ ⚠ same condition
FAT2 p.Pro1817Ser Uncertain significance ★★ ⚠ 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/fat2-p-pro509 (accessed [today's date]).

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