Is FCSK p.Arg1007His (c.3020G>A) pathogenic?

FCSK p.Arg1007His (c.3020G>A) is classified Uncertain significance in FCSK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-25). AlphaMissense: likely benign (0.073); Rare (popmax 0.192%, afr).

How common is FCSK p.Arg1007His (c.3020G>A) in the general population?

FCSK p.Arg1007His (c.3020G>A) is rare (popmax 0.192%, afr) (gnomAD).

What do computational predictors say about FCSK p.Arg1007His (c.3020G>A)?

AlphaMissense predicts likely benign (score 0.073) — an in-silico prediction, not a clinical call.

FCSK p.Arg1007His

c.3020G>A · rs201350190 · VCV2717246

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.073 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.192%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.073	likely benign
REVEL	0.293	indeterminate
SaProt	LLR -5.61	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 -0.035	GERP -1.9
Regional constraint	o/e 0.94	unconstrained · MANE · 16 kb · p 0.027 · regional, not allelic
Overall
CADD	15.82	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 0.192% African / African-American · 144/75,070 alleles

Filtering AF 0.166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.157%

Overall 0.0104% 168/1,614,002 alleles · rare exomes 94/1,461,650 · genomes 74/152,352 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.192%	521
Admixed American	0.01%	10,004
Remaining individualsnot grpmax-eligible	0.0064%	15,626
East Asian	0.00223%	44,884
South Asian	0.0011%	91,088
European (non-Finnish)	0.00102%	98,337

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.Arg1007His
Coding: c.3020G>A
MANE Select: NM_145059
dbSNP: rs201350190
Type: single nucleotide variant
Location: chr16:70479270 (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.Arg1007Cys Uncertain significance ★ ⚠ same residue
FCSK p.Arg1007Leu 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

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-arg1007his (accessed [today's date]).

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