Is FCSK p.Pro4= (c.12G>A) pathogenic?

FCSK p.Pro4= (c.12G>A) is classified Benign in FCSK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-27). Common (popmax 11.1%, afr) — too common for a highly-penetrant pathogenic allele.

FCSK p.Pro4=

Q: How common is FCSK p.Pro4= (c.12G>A) in the general population?

FCSK p.Pro4= (c.12G>A) is common (popmax 11.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.12G>A · rs8044110 · VCV785536

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 11.1%, afr) — too common for a highly-penetrant pathogenic allele

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 -4	GERP -3.1
Overall
CADD	0.189	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 11.1% African / African-American · 8,345/74,902 alleles

Filtering AF 10.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.9%

Overall 0.578% 9,335/1,613,884 alleles · common exomes 4,498/1,461,688 · genomes 4,837/152,196 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	11.1%	9
Remaining individualsnot grpmax-eligible	0.699%	143
Admixed American	0.59%	170
Middle Eastern	0.231%	433
South Asian	0.0275%	3,642
European (non-Finnish)	0.0135%	7,421
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

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.Pro4=
Coding: c.12G>A
MANE Select: NM_145059
dbSNP: rs8044110
Type: single nucleotide variant
Location: chr16:70463202 (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.Pro4Leu 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-pro4 (accessed [today's date]).

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