Is CSTB p.Pro6Ala (c.16C>G) pathogenic?

CSTB p.Pro6Ala (c.16C>G) is classified Uncertain significance in CSTB (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-23). AlphaMissense: likely benign (0.0681); Very rare (popmax 8.77e-05%, nfe); Associated with progressive myoclonus epilepsy.

What condition is associated with CSTB p.Pro6Ala (c.16C>G)?

CSTB p.Pro6Ala (c.16C>G) is associated with progressive myoclonus epilepsy (ClinVar).

How common is CSTB p.Pro6Ala (c.16C>G) in the general population?

CSTB p.Pro6Ala (c.16C>G) is very rare (popmax 8.77e-05%, nfe) (gnomAD).

What do computational predictors say about CSTB p.Pro6Ala (c.16C>G)?

AlphaMissense predicts likely benign (score 0.0681) — an in-silico prediction, not a clinical call.

CSTB p.Pro6Ala

c.16C>G · rs1236504207 · VCV1380284

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0681 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.77e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

progressive myoclonus epilepsy

Computational evidence

Protein change
AlphaMissense	0.0681	likely benign
REVEL	0.171	moderately benign-leaning
SaProt	LLR -8.63	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 -4.5	GERP -4.1
Regional constraint	o/e 0.98	unconstrained · MANE · 2,064 bp · p 0.83 · regional, not allelic
Overall
CADD	0.086	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 8.77e-05% European (non-Finnish) · 1/1,140,454 alleles

Overall 6.54e-05% 1/1,528,470 alleles · very rare exomes 0/1,376,344 · genomes 1/152,126 · joint denominator

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: CSTB
Protein: p.Pro6Ala
Coding: c.16C>G
MANE Select: NM_000100
dbSNP: rs1236504207
Type: single nucleotide variant
Location: chr21:43776254 (GRCh38)
Gene constraint: LOEUF 1.681 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 95.81 · 3 PDB
Residue 6: an α-helix

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

Disease context

progressive myoclonus epilepsy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CSTB p.Pro6Leu Uncertain significance ★ ⚠ same residue
CSTB c.67-1G>C Pathogenic ★★ same condition
CSTB p.Arg68Ter Pathogenic ★★ same condition
CSTB p.Gln22Ter Pathogenic/Likely pathogenic ★★ same condition
CSTB p.Gln46Ter Pathogenic/Likely pathogenic ★★ same condition
CSTB p.Ala49Thr Uncertain significance ★★ same condition
CSTB p.Ala90Thr Uncertain significance ★★ ⚠ same condition
CSTB p.Asn52Ile 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/cstb-p-pro6ala (accessed [today's date]).

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