Is FAT2 p.Phe686Ser (c.2057T>C) pathogenic?

FAT2 p.Phe686Ser (c.2057T>C) is classified Benign in FAT2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.045); Common (popmax 52.9%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with spinocerebellar ataxia 45.

What condition is associated with FAT2 p.Phe686Ser (c.2057T>C)?

FAT2 p.Phe686Ser (c.2057T>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.Phe686Ser (c.2057T>C)?

AlphaMissense predicts likely benign (score 0.045) — an in-silico prediction, not a clinical call.

FAT2 p.Phe686Ser

Q: How common is FAT2 p.Phe686Ser (c.2057T>C) in the general population?

FAT2 p.Phe686Ser (c.2057T>C) is common (popmax 52.9%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2057T>C · rs9324700 · VCV1285258

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.045 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 52.9%, nfe) — 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	0.045	likely benign
REVEL	0.085	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 8.6	GERP -0.099, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 28 kb · p 7.9e-10 · regional, not allelic
Overall
CADD	17.56	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 52.9% European (non-Finnish) · 624,071/1,179,736 alleles

Filtering AF 52.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 52.7%

Overall 50.4% 813,074/1,613,610 alleles · common exomes 739,294/1,461,612 · genomes 73,780/151,998 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	54.7%	2
Ashkenazi Jewishnot grpmax-eligible	53.5%	2
European (non-Finnish)grpmax	52.9%	2
Remaining individualsnot grpmax-eligible	50.6%	2
Middle Eastern	46.7%	2
African / African-American	44.2%	2
Admixed American	37.6%	3
South Asian	36.4%	3
Amishnot grpmax-eligible	35.5%	3
East Asian	32.6%	3

Finnish 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.Phe686Ser
Coding: c.2057T>C
MANE Select: NM_001447
dbSNP: rs9324700
Type: single nucleotide variant
Location: chr5:151566875 (GRCh38)
Gene constraint: LOEUF 0.554 · pLI <0.01 (gnomAD)
Residue 686: 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-phe686ser (accessed [today's date]).

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