Is CTSF p.Arg421Trp (c.1261C>T) pathogenic?

CTSF p.Arg421Trp (c.1261C>T) is classified Benign/Likely benign in CTSF (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.1105); Low-frequency (popmax 2.42%, afr); Associated with Inborn genetic diseases.

What condition is associated with CTSF p.Arg421Trp (c.1261C>T)?

CTSF p.Arg421Trp (c.1261C>T) is associated with Inborn genetic diseases, neuronal ceroid lipofuscinosis 13 (ClinVar).

How common is CTSF p.Arg421Trp (c.1261C>T) in the general population?

CTSF p.Arg421Trp (c.1261C>T) is low-frequency (popmax 2.42%, afr) (gnomAD).

What do computational predictors say about CTSF p.Arg421Trp (c.1261C>T)?

AlphaMissense predicts likely benign (score 0.1105) — an in-silico prediction, not a clinical call.

CTSF p.Arg421Trp

c.1261C>T · rs28464796 · VCV376976

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1105 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.42%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1105	likely benign
REVEL	0.213	benign-leaning
SaProt	LLR -4.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.2	GERP 0.7, phastCons 0.99
Regional constraint	o/e 1.02	unconstrained · MANE · 4,550 bp · p 0.69 · regional, not allelic
Overall
CADD	24.0	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 2.42% African / African-American · 1,816/74,936 alleles

Filtering AF 2.33% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.29%

Overall 0.135% 2,172/1,604,768 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.42%	41
Remaining individualsnot grpmax-eligible	0.171%	586
Admixed American	0.159%	627
Middle Eastern	0.15%	665
Finnishnot grpmax-eligible	0.0682%	1,466
European (non-Finnish)	0.00833%	11,999
South Asian	0.00669%	14,941
East Asian	0.00225%	44,524

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.Arg421Trp
Coding: c.1261C>T
MANE Select: NM_003793
dbSNP: rs28464796
Type: single nucleotide variant
Location: chr11:66564618 (GRCh38)
Gene constraint: LOEUF 1.296 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.78 · 1 PDB
Residue 421: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neuronal ceroid lipofuscinosis 13

Similar variants

CTSF p.Arg421Gln Uncertain significance ★★ ⚠ same residue
CTSF p.Arg421= Likely benign ★ same residue
CTSF c.1045+1G>T Likely pathogenic ★★ same condition
CTSF p.Arg217Ter Pathogenic ★★ same condition
CTSF p.Ala22Ser Uncertain significance ★★ ⚠ same condition
CTSF p.Arg121Pro Uncertain significance ★★ ⚠ same condition
CTSF p.Arg196Gln Uncertain significance ★★ ⚠ same condition
CTSF p.Arg196Trp Uncertain significance ★★ ⚠ same condition

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-arg421trp (accessed [today's date]).

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