Is FMN2 p.Pro403Leu (c.1208C>T) pathogenic?

FMN2 p.Pro403Leu (c.1208C>T) is classified Conflicting classifications of pathogenicity in FMN2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-12-05). AlphaMissense: likely benign (0.1086); Very rare (popmax 0.00127%, nfe).

How common is FMN2 p.Pro403Leu (c.1208C>T) in the general population?

FMN2 p.Pro403Leu (c.1208C>T) is very rare (popmax 0.00127%, nfe) (gnomAD).

What do computational predictors say about FMN2 p.Pro403Leu (c.1208C>T)?

AlphaMissense predicts likely benign (score 0.1086) — an in-silico prediction, not a clinical call.

FMN2 p.Pro403Leu

c.1208C>T · rs762357829 · VCV1336344

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1086 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1086	likely benign
REVEL	0.144	moderately benign-leaning
SaProt	LLR -6.79	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.1	GERP 0.73, phastCons 0.83
Regional constraint	o/e 0.95	unconstrained · MANE · 31 kb · p 0.15 · regional, not allelic
Overall
CADD	17.09	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 0.00127% European (non-Finnish) · 15/1,178,902 alleles

Filtering AF 0.000764% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000606%

Overall 0.000931% 15/1,611,114 alleles · very rare exomes 12/1,458,992 · genomes 3/152,122 · 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: FMN2
Protein: p.Pro403Leu
Coding: c.1208C>T
MANE Select: NM_020066
dbSNP: rs762357829
Type: single nucleotide variant
Location: chr1:240093317 (GRCh38)
Gene constraint: LOEUF 0.51 · pLI 0.51 (gnomAD)
Structure: AlphaFold pLDDT 51.48 · 2 PDB
Residue 403: the 'disordered' region

Full FMN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FMN2 p.Ile183Phe Likely pathogenic ★★ ⚠ same type
FMN2 p.Ala1691Val Uncertain significance ★★ ⚠ same type
FMN2 p.Ala367Val Uncertain significance ★★ ⚠ same type
FMN2 p.Ala508Val Uncertain significance ★★ ⚠ same type
FMN2 p.Asp352Tyr Uncertain significance ★★ ⚠ same type
FMN2 p.Gln192Leu Uncertain significance ★★ ⚠ same type
FMN2 p.Gln210Arg Uncertain significance ★★ ⚠ same type
FMN2 p.Gly244Ala 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/fmn2-p-pro403leu (accessed [today's date]).

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