Is FCSK p.Arg97Ter (c.289C>T) pathogenic?

FCSK p.Arg97Ter (c.289C>T) is classified Uncertain significance in FCSK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-24). Ultra-rare (popmax 0.0183%, amr).

How common is FCSK p.Arg97Ter (c.289C>T) in the general population?

FCSK p.Arg97Ter (c.289C>T) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

FCSK p.Arg97Ter

c.289C>T · rs772939990 · VCV1909872

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 24
Splicing
SpliceAI	Δ0.57	acceptor gain · deltas
Pangolin	Δ0.58	gain · loss 0.50 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.8	GERP 1.7, phastCons 1
Overall
CADD	46.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0183% Admixed American · 11/59,980 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00786%

Overall 0.00304% 49/1,613,586 alleles · ultra-rare exomes 47/1,461,420 · genomes 2/152,166 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,453
European (non-Finnish)	0.00314%	31,886
African / African-American	0.00134%	74,900

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: FCSK
Protein: p.Arg97Ter
Coding: c.289C>T
MANE Select: NM_145059
dbSNP: rs772939990
Type: single nucleotide variant
Location: chr16:70466135 (GRCh38)
Gene constraint: LOEUF 1.254 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.20

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

Similar variants

FCSK p.Arg97Gln Uncertain significance ★ ⚠ same residue
FCSK c.412-2A>G Likely pathogenic ★★ same type
FCSK c.485-2A>G Uncertain significance ★★ same type
FCSK p.Ala297Val Uncertain significance ★★ ⚠ same type
FCSK p.Ala348Ser Uncertain significance ★★ ⚠ same type
FCSK p.Ala481Thr Uncertain significance ★★ ⚠ same type
FCSK p.Ala488Thr Uncertain significance ★★ same type
FCSK p.Ala518Val 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/fcsk-p-arg97ter (accessed [today's date]).

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