Is CTSF p.Val444Ile (c.1330G>A) pathogenic?

CTSF p.Val444Ile (c.1330G>A) is classified Likely benign in CTSF (ClinVar, Single submitter, 1 submitter; last evaluated 2018-03-14). AlphaMissense: likely benign (0.0599); Ultra-rare (popmax 0.0144%, sas); Associated with Inborn genetic diseases.

What condition is associated with CTSF p.Val444Ile (c.1330G>A)?

CTSF p.Val444Ile (c.1330G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CTSF p.Val444Ile (c.1330G>A) in the general population?

CTSF p.Val444Ile (c.1330G>A) is ultra-rare (popmax 0.0144%, sas) (gnomAD).

What do computational predictors say about CTSF p.Val444Ile (c.1330G>A)?

AlphaMissense predicts likely benign (score 0.0599) — an in-silico prediction, not a clinical call.

CTSF p.Val444Ile

c.1330G>A · rs774367919 · VCV1770138

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0599 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0144%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0599	likely benign
REVEL	0.278	benign-leaning
SaProt	LLR -7.41	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 -5	GERP -4.2
Regional constraint	o/e 1.02	unconstrained · MANE · 4,550 bp · p 0.69 · regional, not allelic
Overall
CADD	0.017	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 0.0144% South Asian · 13/90,550 alleles

Filtering AF 0.00849% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00665%

Overall 0.00577% 93/1,611,836 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0144%	6,965
Remaining individualsnot grpmax-eligible	0.00961%	10,402
African / African-American	0.00668%	14,981
European (non-Finnish)	0.00568%	17,600
Admixed American	0.00335%	29,808

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.Val444Ile
Coding: c.1330G>A
MANE Select: NM_003793
dbSNP: rs774367919
Type: single nucleotide variant
Location: chr11:66564138 (GRCh38)
Gene constraint: LOEUF 1.296 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.78 · 1 PDB
Residue 444: a disulfide bond; a β-strand

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-val444ile (accessed [today's date]).

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