Is FTO p.Met1Val (c.1A>G) pathogenic?

FTO p.Met1Val (c.1A>G) is classified Uncertain significance in FTO (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-26). Very rare (popmax 0.00273%, afr); Associated with lethal polymalformative syndrome, Boissel type.

What condition is associated with FTO p.Met1Val (c.1A>G)?

FTO p.Met1Val (c.1A>G) is associated with lethal polymalformative syndrome, Boissel type (ClinVar).

How common is FTO p.Met1Val (c.1A>G) in the general population?

FTO p.Met1Val (c.1A>G) is very rare (popmax 0.00273%, afr) (gnomAD).

FTO p.Met1Val

c.1A>G · rs534074284 · VCV2441589

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00273%, afr)

Conditions

lethal polymalformative syndrome, Boissel type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.383	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.7, phastCons 1
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00273% African / African-American · 2/73,180 alleles

Filtering AF 0.000454% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00017%

Overall 0.000322% 5/1,551,548 alleles · very rare exomes 3/1,399,200 · genomes 2/152,348 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00273%	36,590
Admixed American	0.00196%	51,002
European (non-Finnish)	0.000174%	573,437

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.Met1Val
Coding: c.1A>G
MANE Select: NM_001080432
dbSNP: rs534074284
Type: single nucleotide variant
Location: chr16:53704185 (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

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.Pro93Arg 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-met1val (accessed [today's date]).

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