Is FAT2 p.Pro1817Ser (c.5449C>T) pathogenic?

FAT2 p.Pro1817Ser (c.5449C>T) is classified Uncertain significance in FAT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-30). AlphaMissense: likely benign (0.0818); Very rare (popmax 0.00833%, amr); Associated with spinocerebellar ataxia 45.

What condition is associated with FAT2 p.Pro1817Ser (c.5449C>T)?

FAT2 p.Pro1817Ser (c.5449C>T) is associated with spinocerebellar ataxia 45 (ClinVar).

How common is FAT2 p.Pro1817Ser (c.5449C>T) in the general population?

FAT2 p.Pro1817Ser (c.5449C>T) is very rare (popmax 0.00833%, amr) (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.Pro1817Ser (c.5449C>T)?

AlphaMissense predicts likely benign (score 0.0818) — an in-silico prediction, not a clinical call.

FAT2 p.Pro1817Ser

c.5449C>T · rs761864374 · VCV2411727

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0818 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

spinocerebellar ataxia 45

Computational evidence

Protein change
AlphaMissense	0.0818	likely benign
REVEL	0.141	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 0.062, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 28 kb · p 7.9e-10 · regional, not allelic
Overall
CADD	20.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00833% Admixed American · 5/60,000 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.0013% 21/1,614,016 alleles · very rare exomes 16/1,461,856 · genomes 5/152,160 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0236%	4,229
Admixed Americangrpmax	0.00833%	12,000
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	0.000508%	196,674

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.Pro1817Ser
Coding: c.5449C>T
MANE Select: NM_001447
dbSNP: rs761864374
Type: single nucleotide variant
Location: chr5:151545678 (GRCh38)
Gene constraint: LOEUF 0.554 · pLI <0.01 (gnomAD)
Residue 1817: the cadherin 16 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.Pro1817Leu 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.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-pro1817ser (accessed [today's date]).

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