Is FCSK p.Arg520Ter (c.1558C>T) pathogenic?

FCSK p.Arg520Ter (c.1558C>T) is classified Uncertain significance in FCSK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-27). Ultra-rare (popmax 0.0234%, sas).

How common is FCSK p.Arg520Ter (c.1558C>T) in the general population?

FCSK p.Arg520Ter (c.1558C>T) is ultra-rare (popmax 0.0234%, sas) (gnomAD).

FCSK p.Arg520Ter

c.1558C>T · rs546703026 · VCV1682372

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 0.0234%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 15 of 24
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.091	GERP -3.1
Overall
CADD	35.0	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 0.0234% South Asian · 20/85,440 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0129%

Overall 0.00275% 43/1,564,020 alleles · ultra-rare exomes 33/1,411,704 · genomes 10/152,316 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0234%	4,272
Admixed American	0.0112%	8,940
African / African-American	0.00677%	14,777
East Asian	0.00237%	42,192
Finnishnot grpmax-eligible	0.00178%	56,136
European (non-Finnish)	0.000865%	115,649

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.Arg520Ter
Coding: c.1558C>T
MANE Select: NM_145059
dbSNP: rs546703026
Type: single nucleotide variant
Location: chr16:70473134 (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.Arg520Gln Uncertain significance ★ ⚠ same residue
FCSK p.Arg520fs 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

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-arg520ter (accessed [today's date]).

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