Is FTO p.Arg3Cys (c.7C>T) pathogenic?

FTO p.Arg3Cys (c.7C>T) is classified Uncertain significance in FTO (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-09). AlphaMissense: likely pathogenic (0.749); Very rare (popmax 0.00357%, sas); Associated with Inborn genetic diseases.

What condition is associated with FTO p.Arg3Cys (c.7C>T)?

FTO p.Arg3Cys (c.7C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FTO p.Arg3Cys (c.7C>T) in the general population?

FTO p.Arg3Cys (c.7C>T) is very rare (popmax 0.00357%, sas) (gnomAD).

What do computational predictors say about FTO p.Arg3Cys (c.7C>T)?

AlphaMissense predicts likely pathogenic (score 0.749) — an in-silico prediction, not a clinical call.

FTO p.Arg3Cys

c.7C>T · rs765157936 · VCV2260024

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.749 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00357%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.749	likely pathogenic
REVEL	0.383	indeterminate
SaProt	LLR -12.20	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 4.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 408 kb · p 0.024 · regional, not allelic
Overall
CADD	27.9	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 0.00357% South Asian · 3/84,058 alleles

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

Overall 0.000387% 6/1,551,466 alleles · very rare exomes 6/1,399,174 · genomes 0/152,292 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00357%	28,019
Admixed American	0.00196%	51,004
European (non-Finnish)	0.000174%	573,418

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.Arg3Cys
Coding: c.7C>T
MANE Select: NM_001080432
dbSNP: rs765157936
Type: single nucleotide variant
Location: chr16:53704191 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FTO p.Arg3Pro Uncertain significance ★ ⚠ same residue
FTO c.1239+6T>C Uncertain significance ★★ same condition
FTO p.Ala311Ser Uncertain significance ★★ ⚠ same condition
FTO p.Arg265Gly Uncertain significance ★★ ⚠ same condition
FTO p.Arg473Gln Uncertain significance ★★ ⚠ same condition
FTO p.Arg80Gln Uncertain significance ★★ ⚠ same condition
FTO p.Arg80Trp Uncertain significance ★★ ⚠ same condition
FTO p.Gln339His 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-arg3cys (accessed [today's date]).

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