Is FTO p.Pro93Arg (c.278C>G) pathogenic?

FTO p.Pro93Arg (c.278C>G) is classified Uncertain significance in FTO (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-12). AlphaMissense: likely pathogenic (0.8667); Ultra-rare (popmax 0.0297%, nfe); Associated with lethal polymalformative syndrome, Boissel type.

What condition is associated with FTO p.Pro93Arg (c.278C>G)?

FTO p.Pro93Arg (c.278C>G) is associated with lethal polymalformative syndrome, Boissel type (ClinVar).

How common is FTO p.Pro93Arg (c.278C>G) in the general population?

FTO p.Pro93Arg (c.278C>G) is ultra-rare (popmax 0.0297%, nfe) (gnomAD).

What do computational predictors say about FTO p.Pro93Arg (c.278C>G)?

AlphaMissense predicts likely pathogenic (score 0.8667) — an in-silico prediction, not a clinical call.

FTO p.Pro93Arg

c.278C>G · rs151263395 · VCV888056

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8667 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0297%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

lethal polymalformative syndrome, Boissel type

Computational evidence

Protein change
AlphaMissense	0.8667	likely pathogenic
REVEL	0.506	indeterminate
SaProt	LLR -14.92	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 408 kb · p 0.024 · regional, not allelic
Overall
CADD	26.0	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 0.0297% European (non-Finnish) · 350/1,180,056 alleles

Filtering AF 0.0271% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0261%

Overall 0.0228% 368/1,614,040 alleles · ultra-rare exomes 344/1,461,892 · genomes 24/152,148 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0297%	3,372
Remaining individualsnot grpmax-eligible	0.016%	6,249
African / African-American	0.00534%	18,723
Admixed American	0.005%	19,999
Finnishnot grpmax-eligible	0.00156%	64,032

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.Pro93Arg
Coding: c.278C>G
MANE Select: NM_001080432
dbSNP: rs151263395
Type: single nucleotide variant
Location: chr16:53826018 (GRCh38)
Gene constraint: LOEUF 0.924 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.33 · 28 PDB
Residue 93: the 'fe2og dioxygenase domain' region; a β-strand

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

Disease context

lethal polymalformative syndrome, Boissel type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FTO p.Ala286Val Uncertain significance ★★ ⚠ same condition
FTO p.Arg80Gln Uncertain significance ★★ ⚠ same condition
FTO p.Arg80Trp Uncertain significance ★★ ⚠ same condition
FTO p.Asn143Ser Uncertain significance ★★ ⚠ same condition
FTO p.His62Arg Uncertain significance ★★ ⚠ same condition
FTO p.Met400Val Uncertain significance ★★ ⚠ same condition
FTO p.Pro252Ser Uncertain significance ★★ ⚠ same condition
FTO p.Ser358Phe 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-pro93arg (accessed [today's date]).

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