Is FTO p.Leu44= (c.130C>T) pathogenic?

FTO p.Leu44= (c.130C>T) is classified Likely benign in FTO (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-19). Ultra-rare (popmax 0.01%, amr).

How common is FTO p.Leu44= (c.130C>T) in the general population?

FTO p.Leu44= (c.130C>T) is ultra-rare (popmax 0.01%, amr) (gnomAD).

FTO p.Leu44=

c.130C>T · rs748048648 · VCV2885068

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

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 2.8	GERP 0.93, phastCons 1
Overall
CADD	11.86	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/59,996 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00267% 43/1,611,382 alleles · ultra-rare exomes 36/1,459,238 · genomes 7/152,144 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,999
Remaining individualsnot grpmax-eligible	0.00642%	15,567
European (non-Finnish)	0.0028%	35,751

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.Leu44=
Coding: c.130C>T
MANE Select: NM_001080432
dbSNP: rs748048648
Type: single nucleotide variant
Location: chr16:53825870 (GRCh38)
Gene constraint: LOEUF 0.924 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.33 · 28 PDB
Residue 44: the 'fe2og dioxygenase domain' region; an α-helix

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

Similar variants

FTO c.1239+6T>C Uncertain significance ★★ same type
FTO p.Ala286Val Uncertain significance ★★ ⚠ same type
FTO p.Ala311Ser Uncertain significance ★★ ⚠ same type
FTO p.Arg265Gly Uncertain significance ★★ ⚠ same type
FTO p.Arg473Gln Uncertain significance ★★ ⚠ same type
FTO p.Arg52Ter Uncertain significance ★★ same type
FTO p.Arg80Gln Uncertain significance ★★ ⚠ same type
FTO p.Arg80Trp Uncertain significance ★★ ⚠ same type

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-leu44 (accessed [today's date]).

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