Is FN1 p.Phe697= (c.2091C>T) pathogenic?

FN1 p.Phe697= (c.2091C>T) is classified Benign/Likely benign in FN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-26). Ultra-rare (popmax 0.0168%, mid).

How common is FN1 p.Phe697= (c.2091C>T) in the general population?

FN1 p.Phe697= (c.2091C>T) is ultra-rare (popmax 0.0168%, mid) (gnomAD).

FN1 p.Phe697=

c.2091C>T · rs149878788 · VCV1655360

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 0.95, phastCons 1
Overall
CADD	13.11	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0168% Middle Eastern · 1/5,952 alleles

Filtering AF 0.00394% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00361%

Overall 0.00713% 115/1,613,798 alleles · ultra-rare exomes 103/1,461,704 · genomes 12/152,094 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.132%	759
Remaining individualsnot grpmax-eligible	0.0176%	5,678
Middle Easterngrpmax	0.0168%	5,952
Admixed American	0.00667%	14,999
European (non-Finnish)	0.005%	20,000
South Asian	0.0011%	91,052

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: FN1
Protein: p.Phe697=
Coding: c.2091C>T
MANE Select: NM_212482
dbSNP: rs149878788
Type: single nucleotide variant
Location: chr2:215409965 (GRCh38)
Gene constraint: LOEUF 0.404 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 70.23 · 66 PDB
Residue 697: the fibronectin type-iii 1 domain; a β-strand

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

Similar variants

FN1 p.Cys123Arg Pathogenic/Likely pathogenic ★★ same type
FN1 p.Cys225Trp Pathogenic/Likely pathogenic ★★ same type
FN1 p.Cys231Trp Likely pathogenic ★★ same type
FN1 p.Cys87Trp Pathogenic ★★ same type
FN1 p.Tyr973Cys Pathogenic ★★ same type
FN1 c.2122+4T>C Uncertain significance ★★ same type
FN1 c.2299+3A>T Uncertain significance ★★ same type
FN1 c.3517+1G>A Uncertain significance ★★ same type

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-phe697 (accessed [today's date]).

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