Is FLAD1 p.Arg583Trp (c.1747C>T) pathogenic?

FLAD1 p.Arg583Trp (c.1747C>T) is classified Uncertain significance in FLAD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely pathogenic (0.5865); Very rare (popmax 0.000169%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FLAD1 p.Arg583Trp (c.1747C>T)?

FLAD1 p.Arg583Trp (c.1747C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FLAD1 p.Arg583Trp (c.1747C>T) in the general population?

FLAD1 p.Arg583Trp (c.1747C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about FLAD1 p.Arg583Trp (c.1747C>T)?

AlphaMissense predicts likely pathogenic (score 0.5865) — an in-silico prediction, not a clinical call.

FLAD1 p.Arg583Trp

c.1747C>T · VCV4257896

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5865 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5865	likely pathogenic
REVEL	0.57	indeterminate
SaProt	LLR -16.48	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 9,339 bp · p 0.0044 · regional, not allelic
Overall
CADD	28.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000169% European (non-Finnish) · 2/1,179,964 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,014 alleles · very rare exomes 2/1,461,834 · genomes 0/152,180 · joint denominator

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: FLAD1
Protein: p.Arg583Trp
Coding: c.1747C>T
MANE Select: NM_025207
Type: single nucleotide variant
Location: chr1:154993020 (GRCh38)
Gene constraint: LOEUF 0.809 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.34 · 2 PDB
Residue 583: the 'fad synthase' region; an α-helix

Full FLAD1 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

FLAD1 p.Arg583Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
FLAD1 p.Arg137Gln Uncertain significance ★★ ⚠ same condition
FLAD1 p.Arg137Trp Uncertain significance ★★ ⚠ same condition
FLAD1 p.Arg169His Uncertain significance ★★ ⚠ same condition
FLAD1 p.Arg249Gln Uncertain significance ★★ ⚠ same condition
FLAD1 p.Arg263Gln Uncertain significance ★★ ⚠ same condition
FLAD1 p.Arg306Cys Uncertain significance ★★ ⚠ same condition
FLAD1 p.Arg490Gln Uncertain significance ★★ ⚠ 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/flad1-p-arg583trp (accessed [today's date]).

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