Is FMO4 p.Phe281= (c.843C>T) pathogenic?

FMO4 p.Phe281= (c.843C>T) is classified Benign in FMO4 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-31). Common (popmax 5.22%, eas) — too common for a highly-penetrant pathogenic allele.

FMO4 p.Phe281=

Q: How common is FMO4 p.Phe281= (c.843C>T) in the general population?

FMO4 p.Phe281= (c.843C>T) is common (popmax 5.22%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.843C>T · rs3737926 · VCV708303

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 5.22%, eas) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.8	GERP -3.8
Overall
CADD	0.056	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.22% East Asian · 2,314/44,368 alleles

Filtering AF 5.04% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.97%

Overall 0.175% 2,753/1,571,938 alleles · common exomes 2,413/1,419,670 · genomes 340/152,268 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	5.22%	19
Remaining individualsnot grpmax-eligible	0.25%	401
South Asian	0.245%	409
African / African-American	0.0289%	3,461
Middle Eastern	0.0171%	5,838
Admixed American	0.014%	7,139
European (non-Finnish)	0.00456%	21,947

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: FMO4
Protein: p.Phe281=
Coding: c.843C>T
MANE Select: NM_002022
dbSNP: rs3737926
Type: single nucleotide variant
Location: chr1:171334426 (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.Phe281Leu Uncertain significance ★ ⚠ 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-phe281 (accessed [today's date]).

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