Is HSPB1 p.Pro7= (c.21C>T) pathogenic?

HSPB1 p.Pro7= (c.21C>T) is classified Likely benign in HSPB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-13). Very rare (popmax 0.0017%, nfe); Associated with Charcot-Marie-Tooth disease axonal type 2F.

What condition is associated with HSPB1 p.Pro7= (c.21C>T)?

HSPB1 p.Pro7= (c.21C>T) is associated with Charcot-Marie-Tooth disease axonal type 2F (ClinVar).

How common is HSPB1 p.Pro7= (c.21C>T) in the general population?

HSPB1 p.Pro7= (c.21C>T) is very rare (popmax 0.0017%, nfe) (gnomAD).

HSPB1 p.Pro7=

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

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

c.21C>T · rs759998200 · VCV1154634

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0017%, nfe)

Conditions

Charcot-Marie-Tooth disease axonal type 2F

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.41	GERP -0.87, phastCons 0.065
Overall
CADD	11.19	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0017% European (non-Finnish) · 20/1,179,840 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00125% 20/1,604,390 alleles · very rare exomes 18/1,452,154 · genomes 2/152,236 · 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: HSPB1
Protein: p.Pro7=
Coding: c.21C>T
MANE Select: NM_001540
dbSNP: rs759998200
Type: single nucleotide variant
Location: chr7:76302733 (GRCh38)
Gene constraint: LOEUF 1.888 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.82 · 7 PDB
Residue 7: a UniProt-annotated variant site (in hmnd3; induces hyperphosphorylation of neurofilaments; no effect on cytoplasmic location; no effect on dimerization)

Full HSPB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Elderly

Similar variants

HSPB1 p.Pro7Leu Uncertain significance ★★ ⚠ same residue
HSPB1 p.Pro7Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
HSPB1 p.Pro7Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
HSPB1 p.Pro7Ala Uncertain significance ★ ⚠ same residue
HSPB1 p.Arg127Leu Pathogenic/Likely pathogenic ★★ same condition
HSPB1 p.Arg127Trp Pathogenic ★★ same condition
HSPB1 p.Arg136Gln Pathogenic/Likely pathogenic ★★ same condition
HSPB1 p.Arg136Leu Pathogenic/Likely pathogenic ★★ 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/hspb1-p-pro7 (accessed [today's date]).

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