Is FMO4 p.Val235Phe (c.703G>T) pathogenic?

FMO4 p.Val235Phe (c.703G>T) is classified Uncertain significance in FMO4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-15). AlphaMissense: likely benign (0.0895); Very rare (popmax 0.00133%, afr).

How common is FMO4 p.Val235Phe (c.703G>T) in the general population?

FMO4 p.Val235Phe (c.703G>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about FMO4 p.Val235Phe (c.703G>T)?

AlphaMissense predicts likely benign (score 0.0895) — an in-silico prediction, not a clinical call.

FMO4 p.Val235Phe

c.703G>T · VCV3279358

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0895 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0895	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -2.76	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 -20	GERP -3.8
Regional constraint	o/e 0.95	unconstrained · MANE · 22 kb · p 0.21 · regional, not allelic
Overall
CADD	0.001	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 0.00133% African / African-American · 1/74,988 alleles

Overall 0.000124% 2/1,612,914 alleles · very rare exomes 2/1,460,660 · genomes 0/152,254 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,988
European (non-Finnish)	8.48e-05%	1,179,051

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.Val235Phe
Coding: c.703G>T
MANE Select: NM_002022
Type: single nucleotide variant
Location: chr1:171332784 (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 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
FMO4 p.Arg205Gln 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-val235phe (accessed [today's date]).

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