Is FTO p.Arg80Trp (c.238C>T) pathogenic?

FTO p.Arg80Trp (c.238C>T) is classified Uncertain significance in FTO (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-06). AlphaMissense: likely benign (0.2799); Ultra-rare (popmax 0.0667%, amr); Associated with Inborn genetic diseases.

What condition is associated with FTO p.Arg80Trp (c.238C>T)?

FTO p.Arg80Trp (c.238C>T) is associated with Inborn genetic diseases, lethal polymalformative syndrome, Boissel type (ClinVar).

How common is FTO p.Arg80Trp (c.238C>T) in the general population?

FTO p.Arg80Trp (c.238C>T) is ultra-rare (popmax 0.0667%, amr) (gnomAD).

What do computational predictors say about FTO p.Arg80Trp (c.238C>T)?

AlphaMissense predicts likely benign (score 0.2799) — an in-silico prediction, not a clinical call.

FTO p.Arg80Trp

c.238C>T · rs140101381 · VCV1184333

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2799 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0667%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2799	likely benign
REVEL	0.573	indeterminate
SaProt	LLR -12.49	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; 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	29.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0667% Admixed American · 40/60,008 alleles

Filtering AF 0.0503% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0446%

Overall 0.0142% 230/1,614,130 alleles · ultra-rare exomes 203/1,461,888 · genomes 27/152,242 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0667%	1,500
Remaining individualsnot grpmax-eligible	0.0272%	3,677
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.0143%	6,983
African / African-American	0.004%	25,007

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.Arg80Trp
Coding: c.238C>T
MANE Select: NM_001080432
dbSNP: rs140101381
Type: single nucleotide variant
Location: chr16:53825978 (GRCh38)
Gene constraint: LOEUF 0.924 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.33 · 28 PDB
Residue 80: the 'fe2og dioxygenase domain' region; a β-strand

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

Also linked: lethal polymalformative syndrome, Boissel type

Similar variants

FTO p.Arg80Gln Uncertain significance ★★ ⚠ same residue
FTO c.1239+6T>C Uncertain significance ★★ same condition
FTO p.Ala286Val 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.Asn143Ser 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-arg80trp (accessed [today's date]).

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