Is FTO p.Ala286Val (c.857C>T) pathogenic?

FTO p.Ala286Val (c.857C>T) is classified Uncertain significance in FTO (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-09-27). AlphaMissense: ambiguous (0.3706); Rare (popmax 0.329%, mid); Associated with lethal polymalformative syndrome, Boissel type.

What condition is associated with FTO p.Ala286Val (c.857C>T)?

FTO p.Ala286Val (c.857C>T) is associated with lethal polymalformative syndrome, Boissel type (ClinVar).

How common is FTO p.Ala286Val (c.857C>T) in the general population?

FTO p.Ala286Val (c.857C>T) is rare (popmax 0.329%, mid) (gnomAD).

What do computational predictors say about FTO p.Ala286Val (c.857C>T)?

AlphaMissense predicts ambiguous (score 0.3706) — an in-silico prediction, not a clinical call.

FTO p.Ala286Val

c.857C>T · rs370075174 · VCV885846

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3706 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.329%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

lethal polymalformative syndrome, Boissel type

Computational evidence

Protein change
AlphaMissense	0.3706	ambiguous
REVEL	0.266	benign-leaning
SaProt	LLR -6.75	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 408 kb · p 0.024 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.329% Middle Eastern · 20/6,078 alleles

Filtering AF 0.218% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.182%

Overall 0.011% 178/1,613,030 alleles · rare exomes 163/1,461,094 · genomes 15/151,936 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.329%	304
Ashkenazi Jewishnot grpmax-eligible	0.166%	604
Remaining individualsnot grpmax-eligible	0.032%	3,123
Admixed American	0.025%	3,998
South Asian	0.00769%	13,010
African / African-American	0.00535%	18,706
European (non-Finnish)	0.00534%	18,719

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: FTO
Protein: p.Ala286Val
Coding: c.857C>T
MANE Select: NM_001080432
dbSNP: rs370075174
Type: single nucleotide variant
Location: chr16:53844260 (GRCh38)
Gene constraint: LOEUF 0.924 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.33 · 28 PDB
Residue 286: the 'fe2og dioxygenase domain' region; a β-strand

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

Disease context

lethal polymalformative syndrome, Boissel type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FTO p.Arg80Gln Uncertain significance ★★ ⚠ same condition
FTO p.Arg80Trp Uncertain significance ★★ ⚠ same condition
FTO p.Asn143Ser Uncertain significance ★★ ⚠ same condition
FTO p.His62Arg Uncertain significance ★★ ⚠ same condition
FTO p.Met400Val Uncertain significance ★★ ⚠ same condition
FTO p.Pro252Ser Uncertain significance ★★ ⚠ same condition
FTO p.Pro93Arg Uncertain significance ★★ ⚠ same condition
FTO p.Ser358Phe 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/fto-p-ala286val (accessed [today's date]).

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