Is FTO p.Arg3Pro (c.8G>C) pathogenic?

FTO p.Arg3Pro (c.8G>C) is classified Uncertain significance in FTO (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-02). AlphaMissense: likely pathogenic (0.658); Very rare (popmax 0.00357%, sas).

How common is FTO p.Arg3Pro (c.8G>C) in the general population?

FTO p.Arg3Pro (c.8G>C) is very rare (popmax 0.00357%, sas) (gnomAD).

What do computational predictors say about FTO p.Arg3Pro (c.8G>C)?

AlphaMissense predicts likely pathogenic (score 0.658) — an in-silico prediction, not a clinical call.

FTO p.Arg3Pro

c.8G>C · rs1161946063 · VCV2806123

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.658 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00357%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.658	likely pathogenic
REVEL	0.346	indeterminate
SaProt	LLR -12.05	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 408 kb · p 0.024 · regional, not allelic
Overall
CADD	29.6	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 0.00357% South Asian · 3/84,046 alleles

Filtering AF 0.000948% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000463%

Overall 0.000258% 4/1,551,482 alleles · very rare exomes 4/1,399,166 · genomes 0/152,316 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00357%	28,015
Remaining individualsnot grpmax-eligible	0.00166%	60,096

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.Arg3Pro
Coding: c.8G>C
MANE Select: NM_001080432
dbSNP: rs1161946063
Type: single nucleotide variant
Location: chr16:53704192 (GRCh38)
Gene constraint: LOEUF 0.924 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.33 · 28 PDB

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

Similar variants

FTO p.Arg3Cys 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-arg3pro (accessed [today's date]).

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