Is FMN2 p.Pro1221Ser (c.3661C>T) pathogenic?

FMN2 p.Pro1221Ser (c.3661C>T) is classified Uncertain significance in FMN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-30). AlphaMissense: likely benign (0.0902); Very rare (popmax 0.00674%, afr); Associated with Inborn genetic diseases.

What condition is associated with FMN2 p.Pro1221Ser (c.3661C>T)?

FMN2 p.Pro1221Ser (c.3661C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FMN2 p.Pro1221Ser (c.3661C>T) in the general population?

FMN2 p.Pro1221Ser (c.3661C>T) is very rare (popmax 0.00674%, afr) (gnomAD).

What do computational predictors say about FMN2 p.Pro1221Ser (c.3661C>T)?

AlphaMissense predicts likely benign (score 0.0902) — an in-silico prediction, not a clinical call.

FMN2 p.Pro1221Ser

c.3661C>T · rs751441075 · VCV2505732

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0902 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00674%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0902	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -9.33	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 0.58	GERP -1.6, phastCons 0.78
Regional constraint	o/e 1.12	unconstrained · MANE · 50 kb · p 0.065 · regional, not allelic
Overall
CADD	13.83	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 0.00674% African / African-American · 5/74,132 alleles

Filtering AF 0.00257% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00163%

Overall 0.00031% 5/1,610,376 alleles · very rare

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.Pro1221Ser
Coding: c.3661C>T
MANE Select: NM_020066
dbSNP: rs751441075
Type: single nucleotide variant
Location: chr1:240208473 (GRCh38)
Gene constraint: LOEUF 0.51 · pLI 0.51 (gnomAD)
Structure: AlphaFold pLDDT 51.48 · 2 PDB
Residue 1221: the fh1 domain; the 'disordered' region

Full FMN2 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

FMN2 p.Ala367Val Uncertain significance ★★ ⚠ same condition
FMN2 p.Ala508Val Uncertain significance ★★ ⚠ same condition
FMN2 p.Asp352Tyr Uncertain significance ★★ ⚠ same condition
FMN2 p.Gly244Ala Uncertain significance ★★ ⚠ same condition
FMN2 p.Gly553Arg Uncertain significance ★★ ⚠ same condition
FMN2 p.Lys1681Arg Uncertain significance ★★ ⚠ same condition
FMN2 p.Pro1228Leu Uncertain significance ★★ ⚠ same condition
FMN2 p.Pro232Ala 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/fmn2-p-pro1221ser (accessed [today's date]).

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