Is FMO4 p.Cys63Phe (c.188G>T) pathogenic?

FMO4 p.Cys63Phe (c.188G>T) is classified Uncertain significance in FMO4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-02). AlphaMissense: likely pathogenic (0.8548); Ultra-rare (popmax 0.0165%, mid).

How common is FMO4 p.Cys63Phe (c.188G>T) in the general population?

FMO4 p.Cys63Phe (c.188G>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about FMO4 p.Cys63Phe (c.188G>T)?

AlphaMissense predicts likely pathogenic (score 0.8548) — an in-silico prediction, not a clinical call.

FMO4 p.Cys63Phe

c.188G>T · rs2525971584 · VCV3095901

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8548 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8548	likely pathogenic · top 8% in FMO4
REVEL	0.215	benign-leaning
SaProt	LLR -9.65	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.23 · evaluated, not missing
Pangolin	Δ0.20	gain · loss 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 1	GERP -2.8, phastCons 0.093
Regional constraint	o/e 0.95	unconstrained · MANE · 22 kb · p 0.21 · regional, not allelic
Overall
CADD	23.2	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

Grpmax group 0.0165% Middle Eastern · 1/6,056 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00161% 26/1,613,082 alleles · ultra-rare exomes 26/1,460,842 · genomes 0/152,240 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,056
European (non-Finnish)	0.00212%	47,167

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.Cys63Phe
Coding: c.188G>T
MANE Select: NM_002022
dbSNP: rs2525971584
Type: single nucleotide variant
Location: chr1:171323059 (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-cys63phe (accessed [today's date]).

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