Is FTO p.Ile334= (c.1002T>C) pathogenic?

FTO p.Ile334= (c.1002T>C) is classified Benign in FTO (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-26). Low-frequency (popmax 2.19%, afr); Associated with lethal polymalformative syndrome, Boissel type.

What condition is associated with FTO p.Ile334= (c.1002T>C)?

FTO p.Ile334= (c.1002T>C) is associated with lethal polymalformative syndrome, Boissel type (ClinVar).

How common is FTO p.Ile334= (c.1002T>C) in the general population?

FTO p.Ile334= (c.1002T>C) is low-frequency (popmax 2.19%, afr) (gnomAD).

FTO p.Ile334=

c.1002T>C · rs148109727 · VCV773057

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.19%, afr)

Conditions

lethal polymalformative syndrome, Boissel type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.39	GERP -4.6
Overall
CADD	5.824	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.19% African / African-American · 1,641/75,000 alleles

Filtering AF 2.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.06%

Overall 0.123% 1,993/1,613,970 alleles · low-frequency exomes 1,019/1,461,786 · genomes 974/152,184 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.19%	46
Admixed American	0.213%	469
Middle Eastern	0.198%	505
Remaining individualsnot grpmax-eligible	0.181%	553
South Asian	0.0121%	8,280
European (non-Finnish)	0.00746%	13,408

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.Ile334=
Coding: c.1002T>C
MANE Select: NM_001080432
dbSNP: rs148109727
Type: single nucleotide variant
Location: chr16:53879870 (GRCh38)
Gene constraint: LOEUF 0.924 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.33 · 28 PDB
Residue 334: an α-helix

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.Ala286Val Uncertain significance ★★ ⚠ same condition
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

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-ile334 (accessed [today's date]).

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