Is FTO p.Thr4= (c.12C>G) pathogenic?

FTO p.Thr4= (c.12C>G) is classified Benign/Likely benign in FTO (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-23). Rare (popmax 0.293%, afr).

How common is FTO p.Thr4= (c.12C>G) in the general population?

FTO p.Thr4= (c.12C>G) is rare (popmax 0.293%, afr) (gnomAD).

FTO p.Thr4=

c.12C>G · rs115368866 · VCV754466

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.293%, afr)

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 -0.38	GERP -4.1
Overall
CADD	11.01	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.293% African / African-American · 214/73,156 alleles

Filtering AF 0.26% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.248%

Overall 0.0159% 247/1,551,444 alleles · rare exomes 111/1,399,178 · genomes 136/152,266 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.293%	342
Admixed American	0.0412%	2,428
Remaining individualsnot grpmax-eligible	0.0116%	8,585
European (non-Finnish)	0.000436%	229,365

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.Thr4=
Coding: c.12C>G
MANE Select: NM_001080432
dbSNP: rs115368866
Type: single nucleotide variant
Location: chr16:53704196 (GRCh38)
Gene constraint: LOEUF 0.924 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.33 · 28 PDB
Residue 4: a modified residue (phosphothreonine)

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

Similar variants

FTO p.Thr4Ala Uncertain significance ★ ⚠ same residue
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

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-thr4 (accessed [today's date]).

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