Is FMN2 p.Pro947fs (c.2840del) pathogenic?

FMN2 p.Pro947fs (c.2840del) is classified Likely pathogenic in FMN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-30). Ultra-rare (popmax 0.0539%, nfe); Associated with intellectual disability, autosomal recessive 47.

What condition is associated with FMN2 p.Pro947fs (c.2840del)?

FMN2 p.Pro947fs (c.2840del) is associated with intellectual disability, autosomal recessive 47 (ClinVar).

How common is FMN2 p.Pro947fs (c.2840del) in the general population?

FMN2 p.Pro947fs (c.2840del) is ultra-rare (popmax 0.0539%, nfe) (gnomAD).

FMN2 p.Pro947fs

c.2840del · VCV3779672

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0539%, nfe)

Conditions

intellectual disability, autosomal recessive 47

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -15	GERP -2.1
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	chrX:26504256 segmental duplication, simple repeat · ambiguous alignment · reads may not map uniquely · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0539% European (non-Finnish) · 557/1,032,464 alleles

Filtering AF 0.0502% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0487%

Overall 0.0434% 589/1,355,854 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0645%	1,550
European (non-Finnish)grpmax	0.0539%	1,854
Middle Eastern	0.0239%	4,188
Remaining individualsnot grpmax-eligible	0.0113%	8,863
Admixed American	0.00678%	14,745
African / African-American	0.00513%	19,485
South Asian	0.0042%	23,783
Finnishnot grpmax-eligible	0.00393%	25,477

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro947fs
Coding: c.2840del
MANE Select: NM_020066
Type: Deletion
Location: chr1:240207648 (GRCh38)
Gene constraint: LOEUF 0.51 · pLI 0.51 (gnomAD)
Structure: AlphaFold pLDDT 51.48 · 2 PDB
Residue 947: the fh1 domain; the 'disordered' region

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

Disease context

intellectual disability, autosomal recessive 47 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FMN2 p.Pro517fs Pathogenic/Likely pathogenic ★★ same condition
FMN2 p.Pro947Leu Benign/Likely benign ★★ same residue
FMN2 p.Arg1148_Pro1169del Conflicting classifications of pathogenicity ★ same condition
FMN2 p.Leu948fs Conflicting classifications of pathogenicity ★ same condition
FMN2 p.Pro947_Pro958delinsLeu Uncertain significance ★ same residue
FMN2 p.Pro947= Likely benign ★ same residue
FMN2 p.Pro947Arg Likely benign ★ ⚠ same residue
FMN2 p.Thr839fs Pathogenic 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-pro947fs (accessed [today's date]).

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