Is CTSF p.Lys450Arg (c.1349A>G) pathogenic?

CTSF p.Lys450Arg (c.1349A>G) is classified Uncertain significance in CTSF (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-03). AlphaMissense: likely benign (0.2329); Very rare (popmax 0.00534%, afr).

How common is CTSF p.Lys450Arg (c.1349A>G) in the general population?

CTSF p.Lys450Arg (c.1349A>G) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about CTSF p.Lys450Arg (c.1349A>G)?

AlphaMissense predicts likely benign (score 0.2329) — an in-silico prediction, not a clinical call.

CTSF p.Lys450Arg

c.1349A>G · rs780392718 · VCV1310919

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2329 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2329	likely benign
REVEL	0.45	indeterminate
SaProt	LLR -8.91	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.74	acceptor gain · deltas
Pangolin	Δ0.32	loss · gain 0.31 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 6.1	GERP 2.2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 4,550 bp · p 0.69 · regional, not allelic
Overall
CADD	34.0	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 0.00534% African / African-American · 4/74,934 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.0031% 50/1,613,242 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,734
European (non-Finnish)	0.00356%	28,089
Remaining individualsnot grpmax-eligible	0.0032%	31,226
Admixed American	0.00167%	59,868
Finnishnot grpmax-eligible	0.00156%	63,958

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: CTSF
Protein: p.Lys450Arg
Coding: c.1349A>G
MANE Select: NM_003793
dbSNP: rs780392718
Type: single nucleotide variant
Location: chr11:66564119 (GRCh38)
Gene constraint: LOEUF 1.296 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.78 · 1 PDB
Residue 450: a disulfide bond; a β-strand

Full CTSF gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CTSF c.1045+1G>T Likely pathogenic ★★ same type
CTSF p.Arg217Ter Pathogenic ★★ same type
CTSF p.Ala22Ser Uncertain significance ★★ ⚠ same type
CTSF p.Arg121Pro Uncertain significance ★★ ⚠ same type
CTSF p.Arg196Gln Uncertain significance ★★ ⚠ same type
CTSF p.Arg196Trp Uncertain significance ★★ ⚠ same type
CTSF p.Arg205Trp Uncertain significance ★★ ⚠ same type
CTSF p.Arg413Cys 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/ctsf-p-lys450arg (accessed [today's date]).

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