Is FAT2 p.Phe2428Ser (c.7283T>C) pathogenic?

FAT2 p.Phe2428Ser (c.7283T>C) is classified Benign in FAT2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0474); Common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele; Associated with spinocerebellar ataxia 45.

What condition is associated with FAT2 p.Phe2428Ser (c.7283T>C)?

FAT2 p.Phe2428Ser (c.7283T>C) 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.

What do computational predictors say about FAT2 p.Phe2428Ser (c.7283T>C)?

AlphaMissense predicts likely benign (score 0.0474) — an in-silico prediction, not a clinical call.

FAT2 p.Phe2428Ser

Q: How common is FAT2 p.Phe2428Ser (c.7283T>C) in the general population?

FAT2 p.Phe2428Ser (c.7283T>C) is common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.7283T>C · rs6892335 · VCV1269573

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0474 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

spinocerebellar ataxia 45

Computational evidence

Protein change
AlphaMissense	0.0474	likely benign
REVEL	0.091	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 5.1	GERP 1.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 28 kb · p 7.9e-10 · regional, not allelic
Overall
CADD	19.33	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 100% East Asian · 44,880/44,880 alleles

Filtering AF 99.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 99.2%

Overall 99.5% 1,606,002/1,614,192 alleles · common exomes 1,454,276/1,461,870 · genomes 151,726/152,322 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	100%	1
Ashkenazi Jewishnot grpmax-eligible	100%	1
Middle Eastern	100%	1
Amishnot grpmax-eligible	99.9%	1
African / African-American	99.9%	1
Admixed American	99.8%	1
South Asian	99.8%	1
Finnishnot grpmax-eligible	99.7%	1
Remaining individualsnot grpmax-eligible	99.6%	1
European (non-Finnish)	99.4%	1

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.Phe2428Ser
Coding: c.7283T>C
MANE Select: NM_001447
dbSNP: rs6892335
Type: single nucleotide variant
Location: chr5:151543844 (GRCh38)
Gene constraint: LOEUF 0.554 · pLI <0.01 (gnomAD)
Residue 2428: the cadherin 21 domain; a UniProt-annotated variant site (in)

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.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
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-phe2428ser (accessed [today's date]).

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