Is HSPB8 p.Pro7= (c.21C>A) pathogenic?

HSPB8 p.Pro7= (c.21C>A) is classified Likely benign in HSPB8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-15). Very rare (popmax 8.47e-05%, nfe); Associated with Charcot-Marie-Tooth disease axonal type 2L.

What condition is associated with HSPB8 p.Pro7= (c.21C>A)?

HSPB8 p.Pro7= (c.21C>A) is associated with Charcot-Marie-Tooth disease axonal type 2L (ClinVar).

How common is HSPB8 p.Pro7= (c.21C>A) in the general population?

HSPB8 p.Pro7= (c.21C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

HSPB8 p.Pro7=

Q: How is Autosomal dominant Charcot-Marie-Tooth disease type 2L inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.21C>A · rs2136079832 · VCV1155355

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

Charcot-Marie-Tooth disease axonal type 2L

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.054	GERP -2.7, phastCons 0.8
Overall
CADD	9.488	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,026 alleles

Overall 6.2e-05% 1/1,613,966 alleles · very rare exomes 1/1,461,626 · genomes 0/152,340 · 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: HSPB8
Protein: p.Pro7=
Coding: c.21C>A
MANE Select: NM_014365
dbSNP: rs2136079832
Type: single nucleotide variant
Location: chr12:119179333 (GRCh38)
Gene constraint: LOEUF 0.944 · pLI 0.05 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.50 · 1 PDB

Full HSPB8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease axonal type 2L — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant Charcot-Marie-Tooth disease type 2L (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult

Similar variants

HSPB8 p.Lys141Glu Pathogenic ★★ same condition
HSPB8 c.-172G>C Uncertain significance ★★ same condition
HSPB8 c.-201G>T Uncertain significance ★★ same condition
HSPB8 c.*123G>A Uncertain significance ★★ same condition
HSPB8 p.Ala46Asp Uncertain significance ★★ ⚠ same condition
HSPB8 p.Ala77Thr Uncertain significance ★★ ⚠ same condition
HSPB8 p.Arg17His Uncertain significance ★★ ⚠ same condition
HSPB8 p.Arg29Cys 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/hspb8-p-pro7 (accessed [today's date]).

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