Is FCSK p.Gln697Pro (c.2090A>C) pathogenic?

FCSK p.Gln697Pro (c.2090A>C) is classified Likely benign in FCSK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-24). AlphaMissense: likely benign (0.0478); Ultra-rare (popmax 0.032%, sas).

How common is FCSK p.Gln697Pro (c.2090A>C) in the general population?

FCSK p.Gln697Pro (c.2090A>C) is ultra-rare (popmax 0.032%, sas) (gnomAD).

What do computational predictors say about FCSK p.Gln697Pro (c.2090A>C)?

AlphaMissense predicts likely benign (score 0.0478) — an in-silico prediction, not a clinical call.

FCSK p.Gln697Pro

c.2090A>C · VCV3514536

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0478 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.032%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0478	likely benign
REVEL	0.014	strongly benign-leaning
SaProt	LLR -5.40	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.39	acceptor loss, 2 bp away · masked 0 · deltas
Pangolin	Δ0.27	gain · loss 0.00 · SpliceAI calls loss · independent
Constraint at this position
Conservation	phyloP 0.54	GERP -2, phastCons 0.07
Regional constraint	o/e 0.94	unconstrained · MANE · 16 kb · p 0.027 · regional, not allelic
Overall
CADD	4.803	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 0.032% South Asian · 28/87,462 alleles

Filtering AF 0.0227% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0196%

Overall 0.00201% 32/1,592,014 alleles · ultra-rare exomes 31/1,439,784 · genomes 1/152,230 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.032%	3,124
Remaining individualsnot grpmax-eligible	0.00487%	20,540
European (non-Finnish)	8.55e-05%	1,169,518

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.Gln697Pro
Coding: c.2090A>C
MANE Select: NM_145059
Type: single nucleotide variant
Location: chr16:70474629 (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.Gln697His 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-gln697pro (accessed [today's date]).

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