Is CTSV p.Ala186Asp (c.557C>A) pathogenic?

CTSV p.Ala186Asp (c.557C>A) is classified Uncertain significance in CTSV (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: likely pathogenic (0.9566); Very rare (popmax 0.00134%, afr).

How common is CTSV p.Ala186Asp (c.557C>A) in the general population?

CTSV p.Ala186Asp (c.557C>A) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about CTSV p.Ala186Asp (c.557C>A)?

AlphaMissense predicts likely pathogenic (score 0.9566) — an in-silico prediction, not a clinical call.

CTSV p.Ala186Asp

c.557C>A · VCV4235905

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9566 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9566	likely pathogenic · top 8% in CTSV
REVEL	0.814	moderately pathogenic-leaning
SaProt	LLR -14.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 5,091 bp · p 0.8 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00134% African / African-American · 1/74,860 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,613,910 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,860
European (non-Finnish)	0.000254%	393,342

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: CTSV
Protein: p.Ala186Asp
Coding: c.557C>A
MANE Select: NM_001333
Type: single nucleotide variant
Location: chr9:97036587 (GRCh38)
Gene constraint: LOEUF 1.374 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.13 · 25 PDB
Residue 186: an α-helix; a disulfide bond

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

Similar variants

CTSV p.Ala186Thr Uncertain significance ★ ⚠ same residue
CTSV p.Asn179= Benign ★★ same type
CTSV p.Ala15Asp Uncertain significance ★ ⚠ same type
CTSV p.Ala241Ser Uncertain significance ★ ⚠ same type
CTSV p.Ala241Thr Uncertain significance ★ ⚠ same type
CTSV p.Ala79Val Uncertain significance ★ ⚠ same type
CTSV p.Arg101Gly Uncertain significance ★ ⚠ same type
CTSV p.Arg107His Uncertain significance ★ ⚠ 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/ctsv-p-ala186asp (accessed [today's date]).

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