Is FAT2 p.Pro146Ser (c.436C>T) pathogenic?

FAT2 p.Pro146Ser (c.436C>T) is classified Uncertain significance in FAT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-20). AlphaMissense: likely pathogenic (0.9521); Very rare (popmax 0.00297%, nfe); Associated with spinocerebellar ataxia 45.

What condition is associated with FAT2 p.Pro146Ser (c.436C>T)?

FAT2 p.Pro146Ser (c.436C>T) is associated with spinocerebellar ataxia 45 (ClinVar).

How common is FAT2 p.Pro146Ser (c.436C>T) in the general population?

FAT2 p.Pro146Ser (c.436C>T) is very rare (popmax 0.00297%, nfe) (gnomAD).

How is Spinocerebellar ataxia type 45 inherited?

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

What do computational predictors say about FAT2 p.Pro146Ser (c.436C>T)?

AlphaMissense predicts likely pathogenic (score 0.9521) — an in-silico prediction, not a clinical call.

FAT2 p.Pro146Ser

c.436C>T · rs774592284 · VCV3254986

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9521 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00297%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

spinocerebellar ataxia 45

Computational evidence

Protein change
AlphaMissense	0.9521	likely pathogenic · top 3% in FAT2
REVEL	0.937	strongly pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 28 kb · p 7.9e-10 · regional, not allelic
Overall
CADD	27.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00297% European (non-Finnish) · 35/1,180,038 alleles

Filtering AF 0.00215% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00191%

Overall 0.00223% 36/1,614,008 alleles · very rare exomes 34/1,461,890 · genomes 2/152,118 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00297%	33,715
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Pro146Ser
Coding: c.436C>T
MANE Select: NM_001447
dbSNP: rs774592284
Type: single nucleotide variant
Location: chr5:151568496 (GRCh38)
Gene constraint: LOEUF 0.554 · pLI <0.01 (gnomAD)
Residue 146: the cadherin 1 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.Pro146= Likely benign ★ 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.Pro1817Ser Uncertain significance ★★ ⚠ same condition
FAT2 p.Thr3931Met 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-pro146ser (accessed [today's date]).

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