Is FMN2 p.Leu1237Val (c.3709C>G) pathogenic?

FMN2 p.Leu1237Val (c.3709C>G) is classified Benign in FMN2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-06-18). AlphaMissense: likely benign (0.0888); Low-frequency (popmax 1.88%, afr); Associated with FMN2-related disorder.

What condition is associated with FMN2 p.Leu1237Val (c.3709C>G)?

FMN2 p.Leu1237Val (c.3709C>G) is associated with FMN2-related disorder (ClinVar).

How common is FMN2 p.Leu1237Val (c.3709C>G) in the general population?

FMN2 p.Leu1237Val (c.3709C>G) is low-frequency (popmax 1.88%, afr) (gnomAD).

What do computational predictors say about FMN2 p.Leu1237Val (c.3709C>G)?

AlphaMissense predicts likely benign (score 0.0888) — an in-silico prediction, not a clinical call.

FMN2 p.Leu1237Val

c.3709C>G · VCV3352599

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0888 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.88%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

FMN2-related disorder

Computational evidence

Protein change
AlphaMissense	0.0888	likely benign
REVEL	0.129	moderately benign-leaning
SaProt	LLR -7.71	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 0.47	GERP 0.67, phastCons 0.95
Regional constraint	o/e 1.12	unconstrained · MANE · 50 kb · p 0.065 · regional, not allelic
Overall
CADD	0.779	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 1.88% African / African-American · 1,406/74,696 alleles

Filtering AF 1.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.77%

Overall 0.0965% 1,556/1,612,970 alleles · low-frequency exomes 744/1,461,416 · genomes 812/151,554 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.88%	53
Remaining individualsnot grpmax-eligible	0.114%	880
Admixed American	0.0867%	1,153
Middle Eastern	0.0825%	1,212
South Asian	0.0022%	45,508
European (non-Finnish)	0.0017%	58,982

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.Leu1237Val
Coding: c.3709C>G
MANE Select: NM_020066
Type: single nucleotide variant
Location: chr1:240208521 (GRCh38)
Gene constraint: LOEUF 0.51 · pLI 0.51 (gnomAD)
Structure: AlphaFold pLDDT 51.48 · 2 PDB
Residue 1237: the fh1 domain; the 'disordered' region

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

Disease context

FMN2-related disorder

Similar variants

FMN2 p.Ala951= Likely benign ★★ same condition
FMN2 p.Ala973= Benign/Likely benign ★★ same condition
FMN2 p.Gly1005= Likely benign ★★ same condition
FMN2 p.Gly1007= Likely benign ★★ same condition
FMN2 p.Gly1062= Likely benign ★★ same condition
FMN2 p.Gly941= Likely benign ★★ same condition
FMN2 p.Leu1058= Likely benign ★★ same condition
FMN2 p.Leu1069= Likely benign ★★ 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-leu1237val (accessed [today's date]).

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