Is FMO3 p.Phe440Ser (c.1319T>C) pathogenic?

FMO3 p.Phe440Ser (c.1319T>C) is classified Uncertain significance in FMO3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-27). AlphaMissense: likely benign (0.1822); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with FMO3 p.Phe440Ser (c.1319T>C)?

FMO3 p.Phe440Ser (c.1319T>C) is associated with Inborn genetic diseases (ClinVar).

How common is FMO3 p.Phe440Ser (c.1319T>C) in the general population?

FMO3 p.Phe440Ser (c.1319T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about FMO3 p.Phe440Ser (c.1319T>C)?

AlphaMissense predicts likely benign (score 0.1822) — an in-silico prediction, not a clinical call.

FMO3 p.Phe440Ser

c.1319T>C · VCV3850959

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1822 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1822	likely benign
REVEL	0.198	benign-leaning
SaProt	LLR -8.51	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.58	GERP 1.9
Regional constraint	o/e 1.04	unconstrained · MANE · 25 kb · p 0.27 · regional, not allelic
Overall
CADD	19.07	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00167% Admixed American · 1/60,004 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000743% 12/1,614,090 alleles · very rare exomes 10/1,461,842 · genomes 2/152,248 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,004
European (non-Finnish)	0.000932%	107,274

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.Phe440Ser
Coding: c.1319T>C
MANE Select: NM_001002294
Type: single nucleotide variant
Location: chr1:171117162 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FMO3 p.Tyr430His Uncertain significance ★★ same condition
FMO3 p.Thr532Ile Likely benign ★★ same condition
FMO3 p.Ala10Val Uncertain significance ★ ⚠ same condition
FMO3 p.Ala138Thr Uncertain significance ★ ⚠ same condition
FMO3 p.Ala367Val Uncertain significance ★ ⚠ same condition
FMO3 p.Ala378Val Uncertain significance ★ ⚠ same condition
FMO3 p.Ala458Val Uncertain significance ★ ⚠ same condition
FMO3 p.Arg500Gln Conflicting classifications of pathogenicity ★ ⚠ 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/fmo3-p-phe440ser (accessed [today's date]).

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