Is FCSK p.Pro392Arg (c.1175C>G) pathogenic?

FCSK p.Pro392Arg (c.1175C>G) is classified Uncertain significance in FCSK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-24). AlphaMissense: likely benign (0.1388); Ultra-rare (popmax 0.0252%, nfe); Associated with congenital disorder of glycosylation with defective fucosylation 2.

What condition is associated with FCSK p.Pro392Arg (c.1175C>G)?

FCSK p.Pro392Arg (c.1175C>G) is associated with congenital disorder of glycosylation with defective fucosylation 2 (ClinVar).

How common is FCSK p.Pro392Arg (c.1175C>G) in the general population?

FCSK p.Pro392Arg (c.1175C>G) is ultra-rare (popmax 0.0252%, nfe) (gnomAD).

What do computational predictors say about FCSK p.Pro392Arg (c.1175C>G)?

AlphaMissense predicts likely benign (score 0.1388) — an in-silico prediction, not a clinical call.

FCSK p.Pro392Arg

c.1175C>G · rs200941250 · VCV2773044

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1388 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0252%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital disorder of glycosylation with defective fucosylation 2

Computational evidence

Protein change
AlphaMissense	0.1388	likely benign
REVEL	0.238	benign-leaning
SaProt	LLR -12.50	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	Δ0.23	acceptor loss, 12 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 5.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 16 kb · p 0.027 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0252% European (non-Finnish) · 296/1,173,036 alleles

Filtering AF 0.0229% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0219%

Overall 0.0193% 310/1,602,406 alleles · ultra-rare exomes 294/1,450,072 · genomes 16/152,334 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0252%	3,963
Remaining individualsnot grpmax-eligible	0.0194%	5,158
African / African-American	0.00267%	37,444

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.Pro392Arg
Coding: c.1175C>G
MANE Select: NM_145059
dbSNP: rs200941250
Type: single nucleotide variant
Location: chr16:70471186 (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 p.Pro392Ser Uncertain significance ★ ⚠ same residue
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

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-pro392arg (accessed [today's date]).

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