Is FCSK p.Pro476= (c.1428T>C) pathogenic?

FCSK p.Pro476= (c.1428T>C) is classified Benign in FCSK (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). Common (popmax 76.7%, afr) — too common for a highly-penetrant pathogenic allele; Associated with congenital disorder of glycosylation with defective fucosylation 2.

What condition is associated with FCSK p.Pro476= (c.1428T>C)?

FCSK p.Pro476= (c.1428T>C) is associated with congenital disorder of glycosylation with defective fucosylation 2 (ClinVar).

FCSK p.Pro476=

Q: How common is FCSK p.Pro476= (c.1428T>C) in the general population?

FCSK p.Pro476= (c.1428T>C) is common (popmax 76.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1428T>C · rs7192865 · VCV1285285

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 76.7%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

congenital disorder of glycosylation with defective fucosylation 2

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 -1.1	GERP -1.8
Overall
CADD	0.282	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 76.7% African / African-American · 57,058/74,416 alleles

Filtering AF 76.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 75.9%

Overall 50.2% 801,160/1,597,292 alleles · common exomes 712,323/1,445,328 · genomes 88,837/151,964 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	76.7%	1
East Asian	68.6%	1
Admixed American	60.7%	2
Finnishnot grpmax-eligible	59.1%	2
Amishnot grpmax-eligible	56%	2
Ashkenazi Jewishnot grpmax-eligible	52.8%	2
Remaining individualsnot grpmax-eligible	50.5%	2
European (non-Finnish)	48.1%	2
Middle Eastern	46.6%	2
South Asian	32.3%	3

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.Pro476=
Coding: c.1428T>C
MANE Select: NM_145059
dbSNP: rs7192865
Type: single nucleotide variant
Location: chr16:70473004 (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

congenital disorder of glycosylation with defective fucosylation 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FCSK c.412-2A>G Likely pathogenic ★★ same condition
FCSK p.Ala558Val Uncertain significance ★★ ⚠ same condition
FCSK p.Ala652Val Uncertain significance ★★ ⚠ same condition
FCSK p.Arg32Trp Uncertain significance ★★ ⚠ same condition
FCSK p.Arg527Cys Uncertain significance ★★ ⚠ same condition
FCSK p.Arg547Gln Uncertain significance ★★ ⚠ same condition
FCSK p.Arg605Trp Uncertain significance ★★ same condition
FCSK p.Arg74Gln Uncertain significance ★★ ⚠ 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-pro476 (accessed [today's date]).

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