Is CTSF p.Trp427Arg (c.1279T>C) pathogenic?

CTSF p.Trp427Arg (c.1279T>C) is classified Uncertain significance in CTSF (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-26). AlphaMissense: ambiguous (0.442); Very rare (popmax 0.00333%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CTSF p.Trp427Arg (c.1279T>C)?

CTSF p.Trp427Arg (c.1279T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CTSF p.Trp427Arg (c.1279T>C) in the general population?

CTSF p.Trp427Arg (c.1279T>C) is very rare (popmax 0.00333%, nfe) (gnomAD).

What do computational predictors say about CTSF p.Trp427Arg (c.1279T>C)?

AlphaMissense predicts ambiguous (score 0.442) — an in-silico prediction, not a clinical call.

CTSF p.Trp427Arg

c.1279T>C · rs781257663 · VCV3078764

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.442 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.442	ambiguous
REVEL	0.4	indeterminate
SaProt	LLR -4.29	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 4,550 bp · p 0.69 · regional, not allelic
Overall
CADD	27.9	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 0.00333% European (non-Finnish) · 39/1,171,920 alleles

Filtering AF 0.00249% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00219%

Overall 0.00257% 41/1,596,060 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00333%	30,049
Remaining individualsnot grpmax-eligible	0.00323%	30,913

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.Trp427Arg
Coding: c.1279T>C
MANE Select: NM_003793
dbSNP: rs781257663
Type: single nucleotide variant
Location: chr11:66564600 (GRCh38)
Gene constraint: LOEUF 1.296 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.78 · 1 PDB
Residue 427: a disulfide bond

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 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
CTSF p.Asn213Lys 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-trp427arg (accessed [today's date]).

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