Is FTO p.Arg431Ser (c.1293G>C) pathogenic?

FTO p.Arg431Ser (c.1293G>C) is classified Uncertain significance in FTO (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-05). AlphaMissense: ambiguous (0.3834); Very rare (popmax 0.00266%, afr).

How common is FTO p.Arg431Ser (c.1293G>C) in the general population?

FTO p.Arg431Ser (c.1293G>C) is very rare (popmax 0.00266%, afr) (gnomAD).

What do computational predictors say about FTO p.Arg431Ser (c.1293G>C)?

AlphaMissense predicts ambiguous (score 0.3834) — an in-silico prediction, not a clinical call.

FTO p.Arg431Ser

c.1293G>C · rs1488347423 · VCV1969465

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3834 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00266%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3834	ambiguous
REVEL	0.168	moderately benign-leaning
SaProt	LLR -9.97	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 0.61, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 408 kb · p 0.024 · regional, not allelic
Overall
CADD	20.8	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 0.00266% African / African-American · 2/75,062 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,614,122 alleles · very rare exomes 3/1,461,782 · genomes 0/152,340 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00266%	37,531
Admixed American	0.00167%	60,024

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.Arg431Ser
Coding: c.1293G>C
MANE Select: NM_001080432
dbSNP: rs1488347423
Type: single nucleotide variant
Location: chr16:53934038 (GRCh38)
Gene constraint: LOEUF 0.924 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.33 · 28 PDB
Residue 431: an α-helix

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

Similar variants

FTO p.Arg431Gly 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-arg431ser (accessed [today's date]).

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