Is FMO3 p.Phe59fs (c.174_175insA) pathogenic?

FMO3 p.Phe59fs (c.174175insA) is classified Pathogenic in FMO3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-23). Very rare (popmax 8.48e-05%, nfe).

How common is FMO3 p.Phe59fs (c.174_175insA) in the general population?

FMO3 p.Phe59fs (c.174_175insA) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

FMO3 p.Phe59fs

c.174_175insA · rs2526312925 · VCV2840209

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 9
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.7	GERP -3.7

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,878 alleles

Overall 6.2e-05% 1/1,613,910 alleles · very rare exomes 1/1,461,674 · genomes 0/152,236 · joint denominator

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: FMO3
Protein: p.Phe59fs
Coding: c.174_175insA
MANE Select: NM_001002294
dbSNP: rs2526312925
Type: Insertion
Location: chr1:171103826 (GRCh38)
Gene constraint: LOEUF 1.314 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.50

Full FMO3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FMO3 p.Val257delinsArgTer Pathogenic ★ 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/fmo3-p-phe59fs (accessed [today's date]).

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