Is CTSF p.Arg413His (c.1238G>A) pathogenic?

CTSF p.Arg413His (c.1238G>A) is classified Uncertain significance in CTSF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely benign (0.1123); Ultra-rare (popmax 0.0199%, sas); Associated with Inborn genetic diseases.

What condition is associated with CTSF p.Arg413His (c.1238G>A)?

CTSF p.Arg413His (c.1238G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CTSF p.Arg413His (c.1238G>A) in the general population?

CTSF p.Arg413His (c.1238G>A) is ultra-rare (popmax 0.0199%, sas) (gnomAD).

What do computational predictors say about CTSF p.Arg413His (c.1238G>A)?

AlphaMissense predicts likely benign (score 0.1123) — an in-silico prediction, not a clinical call.

CTSF p.Arg413His

c.1238G>A · VCV4235859

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1123 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0199%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1123	likely benign
REVEL	0.169	moderately benign-leaning
SaProt	LLR -6.28	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 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 4,550 bp · p 0.69 · regional, not allelic
Overall
CADD	29.2	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 0.0199% South Asian · 18/90,510 alleles

Filtering AF 0.0128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00211% 34/1,610,234 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0199%	5,028
Middle Eastern	0.0165%	6,046
East Asian	0.00447%	22,376
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,514
African / African-American	0.00133%	74,982
European (non-Finnish)	0.000934%	107,116

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.Arg413His
Coding: c.1238G>A
MANE Select: NM_003793
Type: single nucleotide variant
Location: chr11:66564641 (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

Similar variants

CTSF p.Arg413Cys Uncertain significance ★★ ⚠ same residue
CTSF c.1045+1G>T Likely pathogenic ★★ same condition
CTSF p.Arg217Ter Pathogenic ★★ same condition
CTSF p.Arg121Pro Uncertain significance ★★ ⚠ same condition
CTSF p.Arg196Trp Uncertain significance ★★ ⚠ same condition
CTSF p.Arg418Cys Uncertain significance ★★ ⚠ same condition
CTSF p.Arg421Gln Uncertain significance ★★ ⚠ same condition
CTSF p.Arg54Gly 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-arg413his (accessed [today's date]).

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