Is FCSK p.Arg137= (c.409C>A) pathogenic?

FCSK p.Arg137= (c.409C>A) is classified Likely benign in FCSK (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-09-16). Very rare (popmax 0.00167%, amr); Associated with FCSK-related disorder.

What condition is associated with FCSK p.Arg137= (c.409C>A)?

FCSK p.Arg137= (c.409C>A) is associated with FCSK-related disorder (ClinVar).

How common is FCSK p.Arg137= (c.409C>A) in the general population?

FCSK p.Arg137= (c.409C>A) is very rare (popmax 0.00167%, amr) (gnomAD).

FCSK p.Arg137=

c.409C>A · VCV3351569

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

FCSK-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.7	GERP 1.7, phastCons 1
Overall
CADD	17.75	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,006 alleles

Overall 0.000124% 2/1,613,880 alleles · very rare exomes 2/1,461,558 · genomes 0/152,322 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,006
Remaining individualsnot grpmax-eligible	0.0016%	62,490

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.Arg137=
Coding: c.409C>A
MANE Select: NM_145059
Type: single nucleotide variant
Location: chr16:70466255 (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

Disease context

FCSK-related disorder

Similar variants

FCSK p.Arg137Trp Uncertain significance ★ ⚠ same residue
FCSK p.Arg784Gln Conflicting classifications of pathogenicity ★ ⚠ same condition
FCSK p.Pro375Arg Conflicting classifications of pathogenicity ★ ⚠ same condition
FCSK p.Gln992Ter Uncertain significance same condition
FCSK c.-8T>G Benign same condition
FCSK p.Leu154= Likely benign same condition
FCSK p.Leu500= Likely benign same condition
FCSK p.Phe463= Likely benign 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/fcsk-p-arg137 (accessed [today's date]).

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