Is FCSK p.Arg965Pro (c.2894G>C) pathogenic?

FCSK p.Arg965Pro (c.2894G>C) is classified Uncertain significance in FCSK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-04). AlphaMissense: ambiguous (0.418); Very rare (popmax 0.00667%, amr).

How common is FCSK p.Arg965Pro (c.2894G>C) in the general population?

FCSK p.Arg965Pro (c.2894G>C) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about FCSK p.Arg965Pro (c.2894G>C)?

AlphaMissense predicts ambiguous (score 0.418) — an in-silico prediction, not a clinical call.

FCSK p.Arg965Pro

c.2894G>C · rs761231496 · VCV1990880

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.418 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Computational evidence

Protein change
AlphaMissense	0.418	ambiguous
REVEL	0.573	indeterminate
SaProt	LLR -10.95	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.7	GERP -3.1
Regional constraint	o/e 0.94	unconstrained · MANE · 16 kb · p 0.027 · regional, not allelic
Overall
CADD	0.036	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 0.00667% Admixed American · 4/60,012 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000248% 4/1,613,700 alleles · very rare exomes 4/1,461,390 · genomes 0/152,310 · joint denominator

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.Arg965Pro
Coding: c.2894G>C
MANE Select: NM_145059
dbSNP: rs761231496
Type: single nucleotide variant
Location: chr16:70478615 (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.Arg965Trp Uncertain significance ★★ ⚠ same residue
FCSK p.Arg965Gln 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

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-arg965pro (accessed [today's date]).

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