Is FCSK p.Pro756Arg (c.2267C>G) pathogenic?

FCSK p.Pro756Arg (c.2267C>G) is classified Uncertain significance in FCSK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-06). AlphaMissense: likely benign (0.0786); Very rare (popmax 0.00492%, nfe).

How common is FCSK p.Pro756Arg (c.2267C>G) in the general population?

FCSK p.Pro756Arg (c.2267C>G) is very rare (popmax 0.00492%, nfe) (gnomAD).

What do computational predictors say about FCSK p.Pro756Arg (c.2267C>G)?

AlphaMissense predicts likely benign (score 0.0786) — an in-silico prediction, not a clinical call.

FCSK p.Pro756Arg

c.2267C>G · rs371988447 · VCV1682391

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0786 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00492%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0786	likely benign
REVEL	0.298	indeterminate
SaProt	LLR -7.48	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.7	GERP -2.8
Regional constraint	o/e 0.94	unconstrained · MANE · 16 kb · p 0.027 · regional, not allelic
Overall
CADD	1.155	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00492% European (non-Finnish) · 58/1,178,466 alleles

Filtering AF 0.00386% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00353%

Overall 0.00367% 59/1,609,258 alleles · very rare exomes 55/1,457,022 · genomes 4/152,236 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00492%	20,318
Remaining individualsnot grpmax-eligible	0.00161%	62,212

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.Pro756Arg
Coding: c.2267C>G
MANE Select: NM_145059
dbSNP: rs371988447
Type: single nucleotide variant
Location: chr16:70474901 (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.Pro756Leu Conflicting classifications of pathogenicity ★ ⚠ 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-pro756arg (accessed [today's date]).

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