Is HSPB1 p.Phe33= (c.99C>T) pathogenic?

HSPB1 p.Phe33= (c.99C>T) is classified Likely benign in HSPB1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-07-11). Very rare (popmax 0.00335%, amr); Associated with Charcot-Marie-Tooth disease axonal type 2F.

What condition is associated with HSPB1 p.Phe33= (c.99C>T)?

HSPB1 p.Phe33= (c.99C>T) is associated with Charcot-Marie-Tooth disease axonal type 2F (ClinVar).

How common is HSPB1 p.Phe33= (c.99C>T) in the general population?

HSPB1 p.Phe33= (c.99C>T) is very rare (popmax 0.00335%, amr) (gnomAD).

HSPB1 p.Phe33=

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.99C>T · rs762032846 · VCV220380

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00335%, amr)

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 1	GERP 0.42, phastCons 1
Overall
CADD	14.53	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00335% Admixed American · 2/59,754 alleles

Filtering AF 0.000555% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000208%

Overall 0.000124% 2/1,607,574 alleles · very rare exomes 2/1,455,242 · genomes 0/152,332 · 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.Phe33=
Coding: c.99C>T
MANE Select: NM_001540
dbSNP: rs762032846
Type: single nucleotide variant
Location: chr7:76302811 (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.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
HSPB1 p.Pro182Ala 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-phe33 (accessed [today's date]).

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