Is HSPB1 p.Pro59= (c.177C>T) pathogenic?

HSPB1 p.Pro59= (c.177C>T) is classified Likely benign in HSPB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-17). Very rare (popmax 0.000431%, nfe); Associated with Charcot-Marie-Tooth disease axonal type 2F.

What condition is associated with HSPB1 p.Pro59= (c.177C>T)?

HSPB1 p.Pro59= (c.177C>T) is associated with Charcot-Marie-Tooth disease axonal type 2F (ClinVar).

How common is HSPB1 p.Pro59= (c.177C>T) in the general population?

HSPB1 p.Pro59= (c.177C>T) is very rare (popmax 0.000431%, nfe) (gnomAD).

HSPB1 p.Pro59=

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.177C>T · rs996702771 · VCV2722453

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000431%, 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 0.54	GERP 0.38, phastCons 0.75
Overall
CADD	12.62	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000431% European (non-Finnish) · 5/1,159,136 alleles

Filtering AF 0.000126% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.2e-05%

Overall 0.00032% 5/1,561,062 alleles · very rare exomes 4/1,408,846 · genomes 1/152,216 · 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.Pro59=
Coding: c.177C>T
MANE Select: NM_001540
dbSNP: rs996702771
Type: single nucleotide variant
Location: chr7:76302889 (GRCh38)
Gene constraint: LOEUF 1.888 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.82 · 7 PDB

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.Pro59Ser Uncertain significance ★★ ⚠ same residue
HSPB1 p.Pro59Thr 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
HSPB1 p.Arg140Gly Pathogenic ★★ same condition
HSPB1 p.Gln175Ter 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-pro59 (accessed [today's date]).

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