Is FTO p.Gln385Pro (c.1154A>C) pathogenic?

FTO p.Gln385Pro (c.1154A>C) is classified Uncertain significance in FTO (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-06-03). AlphaMissense: likely pathogenic (0.8533); Very rare (popmax 0.000169%, nfe); Associated with Meniere disease.

What condition is associated with FTO p.Gln385Pro (c.1154A>C)?

FTO p.Gln385Pro (c.1154A>C) is associated with Meniere disease (ClinVar).

How common is FTO p.Gln385Pro (c.1154A>C) in the general population?

FTO p.Gln385Pro (c.1154A>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about FTO p.Gln385Pro (c.1154A>C)?

AlphaMissense predicts likely pathogenic (score 0.8533) — an in-silico prediction, not a clinical call.

FTO p.Gln385Pro

c.1154A>C · rs757468268 · VCV3238918

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8533 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Meniere disease

Computational evidence

Protein change
AlphaMissense	0.8533	likely pathogenic
REVEL	0.702	pathogenic-leaning
SaProt	LLR -10.63	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 408 kb · p 0.024 · regional, not allelic
Overall
CADD	28.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,952 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,072 alleles · very rare exomes 2/1,461,768 · genomes 0/152,304 · joint denominator

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.Gln385Pro
Coding: c.1154A>C
MANE Select: NM_001080432
dbSNP: rs757468268
Type: single nucleotide variant
Location: chr16:53888866 (GRCh38)
Gene constraint: LOEUF 0.924 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.33 · 28 PDB
Residue 385: a turn

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

Disease context

Meniere disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FTO p.His62Arg Uncertain significance ★★ ⚠ same condition
FTO p.Arg96His Uncertain significance ★ ⚠ same condition
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

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-gln385pro (accessed [today's date]).

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