Is FMO4 p.Phe281Leu (c.841T>C) pathogenic?

FMO4 p.Phe281Leu (c.841T>C) is classified Uncertain significance in FMO4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-16). AlphaMissense: ambiguous (0.3761); Absent from gnomAD v4.1.

How common is FMO4 p.Phe281Leu (c.841T>C) in the general population?

FMO4 p.Phe281Leu (c.841T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FMO4 p.Phe281Leu (c.841T>C)?

AlphaMissense predicts ambiguous (score 0.3761) — an in-silico prediction, not a clinical call.

FMO4 p.Phe281Leu

c.841T>C · rs1011072210 · VCV3095907

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3761 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3761	ambiguous
REVEL	0.038	moderately benign-leaning
SaProt	LLR -4.74	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 -5.3	GERP -3.8
Regional constraint	o/e 0.95	unconstrained · MANE · 22 kb · p 0.21 · regional, not allelic
Overall
CADD	0.04	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FMO4
Protein: p.Phe281Leu
Coding: c.841T>C
MANE Select: NM_002022
dbSNP: rs1011072210
Type: single nucleotide variant
Location: chr1:171334424 (GRCh38)
Gene constraint: LOEUF 1.329 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.52

Full FMO4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FMO4 p.Phe281= Benign ★ same residue
FMO4 c.1180+3A>G Uncertain significance ★★ same type
FMO4 p.Gly372Ser Likely benign ★★ same type
FMO4 p.Leu221His Likely benign ★★ same type
FMO4 p.Ser534Pro Benign ★★ same type
FMO4 p.Ala159Asp Uncertain significance ★ ⚠ same type
FMO4 p.Arg116Ser Uncertain significance ★ ⚠ same type
FMO4 p.Arg186Cys 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/fmo4-p-phe281leu (accessed [today's date]).

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