Is CTSO p.Ala43Val (c.128C>T) pathogenic?

CTSO p.Ala43Val (c.128C>T) is classified Uncertain significance in CTSO (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-14). AlphaMissense: ambiguous (0.372); Ultra-rare (popmax 0.0649%, nfe).

How common is CTSO p.Ala43Val (c.128C>T) in the general population?

CTSO p.Ala43Val (c.128C>T) is ultra-rare (popmax 0.0649%, nfe) (gnomAD).

What do computational predictors say about CTSO p.Ala43Val (c.128C>T)?

AlphaMissense predicts ambiguous (score 0.372) — an in-silico prediction, not a clinical call.

CTSO p.Ala43Val

c.128C>T · rs781781958 · VCV2351720

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.372 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0649%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.372	ambiguous
REVEL	0.114	moderately benign-leaning
SaProt	LLR -4.94	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 1.3, phastCons 1
Overall
CADD	24.1	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 0.0649% European (non-Finnish) · 656/1,010,536 alleles

Filtering AF 0.0607% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0591%

Overall 0.0538% 685/1,272,886 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0649%	1,540
Remaining individualsnot grpmax-eligible	0.0464%	2,154
Admixed American	0.0167%	6,002
African / African-American	0.00463%	21,581

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: CTSO
Protein: p.Ala43Val
Coding: c.128C>T
MANE Select: NM_000396 · reported on NM_001334
dbSNP: rs781781958
Type: single nucleotide variant
Location: chr4:155953720 (GRCh38)
Structure: AlphaFold pLDDT 94.89 · 70 PDB
Residue 43: an α-helix

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

Similar variants

CTSK p.Glu43Ter Likely pathogenic ★ same residue
CTSK c.121-1G>A Pathogenic/Likely pathogenic ★★ same type
CTSK c.121-2A>G Pathogenic/Likely pathogenic ★★ same type
CTSK c.244-29A>G Pathogenic/Likely pathogenic ★★ same type
CTSK c.244-2A>C Likely pathogenic ★★ same type
CTSK c.400-1G>C Likely pathogenic ★★ same type
CTSK c.784+1G>A Likely pathogenic ★★ same type
CTSK p.Ala277Val Pathogenic ★★ same type

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/ctso-p-ala43val (accessed [today's date]).

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