Is FN1 p.Arg2001His (c.6002G>A) pathogenic?

FN1 p.Arg2001His (c.6002G>A) is classified Conflicting classifications of pathogenicity in FN1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-04-19). AlphaMissense: likely benign (0.0631); Ultra-rare (popmax 0.0103%, nfe); Associated with glomerulopathy with fibronectin deposits 2.

What condition is associated with FN1 p.Arg2001His (c.6002G>A)?

FN1 p.Arg2001His (c.6002G>A) is associated with glomerulopathy with fibronectin deposits 2, spondylometaphyseal dysplasia, 'corner fracture' type (ClinVar).

How common is FN1 p.Arg2001His (c.6002G>A) in the general population?

FN1 p.Arg2001His (c.6002G>A) is ultra-rare (popmax 0.0103%, nfe) (gnomAD).

How is Fibronectin glomerulopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about FN1 p.Arg2001His (c.6002G>A)?

AlphaMissense predicts likely benign (score 0.0631) — an in-silico prediction, not a clinical call.

FN1 p.Arg2001His

c.6002G>A · rs749462589 · VCV1392753

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0631 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0103%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glomerulopathy with fibronectin deposits 2

Computational evidence

Protein change
AlphaMissense	0.0631	likely benign
REVEL	0.1	moderately benign-leaning
SaProt	LLR -8.93	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 -3.3	GERP -3.6
Regional constraint	o/e 0.90	unconstrained · MANE · 45 kb · p 4.5e-06 · regional, not allelic
Overall
CADD	9.195	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 0.0103% European (non-Finnish) · 122/1,179,988 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00828%

Overall 0.00799% 129/1,613,530 alleles · ultra-rare exomes 124/1,461,862 · genomes 5/151,668 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0103%	9,672
East Asian	0.00447%	22,371
Remaining individualsnot grpmax-eligible	0.0032%	31,242
African / African-American	0.00267%	37,399
South Asian	0.0011%	91,040

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: FN1
Protein: p.Arg2001His
Coding: c.6002G>A
MANE Select: NM_212482
dbSNP: rs749462589
Type: single nucleotide variant
Location: chr2:215375369 (GRCh38)
Gene constraint: LOEUF 0.404 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.23 · 66 PDB
Residue 2001: the fibronectin type-iii 16 domain; a β-strand; the 'heparin-binding 2' region; the 'binds to fbln1' region

Full FN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

glomerulopathy with fibronectin deposits 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: spondylometaphyseal dysplasia, 'corner fracture' type

For Fibronectin glomerulopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages

Similar variants

FN1 p.Arg2001Cys Uncertain significance ★★ ⚠ same residue
FN1 p.Cys123Arg Pathogenic/Likely pathogenic ★★ same condition
FN1 p.Cys225Trp Pathogenic/Likely pathogenic ★★ same condition
FN1 p.Cys231Trp Likely pathogenic ★★ same condition
FN1 p.Cys87Trp Pathogenic ★★ same condition
FN1 p.Tyr973Cys Pathogenic ★★ same condition
FN1 c.2122+4T>C Uncertain significance ★★ same condition
FN1 c.2299+3A>T 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/fn1-p-arg2001his (accessed [today's date]).

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