Is CTSF p.Arg418His (c.1253G>A) pathogenic?

CTSF p.Arg418His (c.1253G>A) is classified Conflicting classifications of pathogenicity in CTSF (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-10-15). AlphaMissense: likely benign (0.0514); Ultra-rare (popmax 0.0166%, mid); Associated with Inborn genetic diseases.

What condition is associated with CTSF p.Arg418His (c.1253G>A)?

CTSF p.Arg418His (c.1253G>A) is associated with Inborn genetic diseases, neuronal ceroid lipofuscinosis 13 (ClinVar).

How common is CTSF p.Arg418His (c.1253G>A) in the general population?

CTSF p.Arg418His (c.1253G>A) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about CTSF p.Arg418His (c.1253G>A)?

AlphaMissense predicts likely benign (score 0.0514) — an in-silico prediction, not a clinical call.

CTSF p.Arg418His

c.1253G>A · rs141345438 · VCV587775

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0514 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0514	likely benign
REVEL	0.228	benign-leaning
SaProt	LLR 1.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.32	GERP -0.27, phastCons 0.34
Regional constraint	o/e 1.02	unconstrained · MANE · 4,550 bp · p 0.69 · regional, not allelic
Overall
CADD	13.28	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 0.0166% Middle Eastern · 1/6,008 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.00299% 48/1,606,654 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,008
African / African-American	0.012%	8,313
Remaining individualsnot grpmax-eligible	0.00965%	10,361
Admixed American	0.00511%	19,586
South Asian	0.00445%	22,490
European (non-Finnish)	0.00204%	49,032
Finnishnot grpmax-eligible	0.00158%	63,220

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.Arg418His
Coding: c.1253G>A
MANE Select: NM_003793
dbSNP: rs141345438
Type: single nucleotide variant
Location: chr11:66564626 (GRCh38)
Gene constraint: LOEUF 1.296 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.78 · 1 PDB

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.Arg418Cys Uncertain significance ★★ ⚠ 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
CTSF p.Arg205Trp 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-arg418his (accessed [today's date]).

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