Is HSPB1 p.Pro36= (c.108C>G) pathogenic?

HSPB1 p.Pro36= (c.108C>G) is classified Benign/Likely benign in HSPB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Ultra-rare (popmax 0.0558%, eas); Associated with neuronopathy, distal hereditary motor, type 2B.

What condition is associated with HSPB1 p.Pro36= (c.108C>G)?

HSPB1 p.Pro36= (c.108C>G) is associated with neuronopathy, distal hereditary motor, type 2B, Charcot-Marie-Tooth disease axonal type 2F (ClinVar).

How common is HSPB1 p.Pro36= (c.108C>G) in the general population?

HSPB1 p.Pro36= (c.108C>G) is ultra-rare (popmax 0.0558%, eas) (gnomAD).

How is Distal hereditary motor neuropathy type 2 inherited?

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

HSPB1 p.Pro36=

c.108C>G · rs765197724 · VCV909658

Benign/Likely benign Single submitter

Classification

Benign/Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0558%, eas)

Conditions

neuronopathy, distal hereditary motor, type 2B

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 -1	GERP -3, phastCons 0.001
Overall
CADD	7.991	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0558% East Asian · 25/44,764 alleles

Filtering AF 0.0388% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0331%

Overall 0.00156% 25/1,606,780 alleles · ultra-rare exomes 23/1,454,450 · genomes 2/152,330 · 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.Pro36=
Coding: c.108C>G
MANE Select: NM_001540
dbSNP: rs765197724
Type: single nucleotide variant
Location: chr7:76302820 (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

neuronopathy, distal hereditary motor, type 2B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease axonal type 2F

For Distal hereditary motor neuropathy type 2 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

HSPB1 p.Pro36Ser 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
HSPB1 p.Gly84Arg 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-pro36 (accessed [today's date]).

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