Is FMN2 p.Arg656Cys (c.1966C>T) pathogenic?

FMN2 p.Arg656Cys (c.1966C>T) is classified Conflicting classifications of pathogenicity in FMN2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-08-14). AlphaMissense: likely benign (0.0638); Ultra-rare (popmax 0.0825%, eas); Associated with Inborn genetic diseases.

What condition is associated with FMN2 p.Arg656Cys (c.1966C>T)?

FMN2 p.Arg656Cys (c.1966C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FMN2 p.Arg656Cys (c.1966C>T) in the general population?

FMN2 p.Arg656Cys (c.1966C>T) is ultra-rare (popmax 0.0825%, eas) (gnomAD).

What do computational predictors say about FMN2 p.Arg656Cys (c.1966C>T)?

AlphaMissense predicts likely benign (score 0.0638) — an in-silico prediction, not a clinical call.

FMN2 p.Arg656Cys

c.1966C>T · rs199730080 · VCV218763

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0638 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0825%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0638	likely benign
REVEL	0.309	indeterminate
SaProt	LLR -6.55	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.4	GERP -4.1
Regional constraint	o/e 1.03	unconstrained · MANE · 84 kb · p 0.48 · regional, not allelic
Overall
CADD	0.095	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 0.0825% East Asian · 37/44,864 alleles

Filtering AF 0.0615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0542%

Overall 0.0131% 211/1,613,848 alleles · ultra-rare exomes 192/1,461,638 · genomes 19/152,210 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0825%	1,213
European (non-Finnish)	0.0128%	7,814
African / African-American	0.012%	8,334
Admixed American	0.0117%	8,570
Remaining individualsnot grpmax-eligible	0.0048%	20,829
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,590
South Asian	0.00329%	30,353

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.Arg656Cys
Coding: c.1966C>T
MANE Select: NM_020066
dbSNP: rs199730080
Type: single nucleotide variant
Location: chr1:240188242 (GRCh38)
Gene constraint: LOEUF 0.51 · pLI 0.51 (gnomAD)
Structure: AlphaFold pLDDT 51.48 · 2 PDB
Residue 656: 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

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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-arg656cys (accessed [today's date]).

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