Is HSPB3 p.Phe80= (c.240C>T) pathogenic?

HSPB3 p.Phe80= (c.240C>T) is classified Likely benign in HSPB3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-07). Very rare (popmax 0.00203%, nfe); Associated with neuronopathy, distal hereditary motor, type 2C.

What condition is associated with HSPB3 p.Phe80= (c.240C>T)?

HSPB3 p.Phe80= (c.240C>T) is associated with neuronopathy, distal hereditary motor, type 2C (ClinVar).

How common is HSPB3 p.Phe80= (c.240C>T) in the general population?

HSPB3 p.Phe80= (c.240C>T) is very rare (popmax 0.00203%, nfe) (gnomAD).

How is Distal hereditary motor neuropathy type 2 inherited?

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

HSPB3 p.Phe80=

c.240C>T · rs760600821 · VCV538751

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00203%, nfe)

Conditions

neuronopathy, distal hereditary motor, type 2C

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 1.7	GERP -0.17, phastCons 1
Overall
CADD	13.63	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00203% European (non-Finnish) · 24/1,180,004 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00248% 40/1,613,906 alleles · very rare exomes 35/1,461,878 · genomes 5/152,028 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0473%	2,115
Remaining individualsnot grpmax-eligible	0.0032%	31,243
European (non-Finnish)grpmax	0.00203%	49,167

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: HSPB3
Protein: p.Phe80=
Coding: c.240C>T
MANE Select: NM_006308
dbSNP: rs760600821
Type: single nucleotide variant
Location: chr5:54456029 (GRCh38)
Gene constraint: LOEUF 1.434 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.30 · 1 PDB
Residue 80: the shsp domain

Full HSPB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Distal hereditary motor neuropathy type 2 (Orphanet):

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

Similar variants

HSPB3 p.Arg23Gln Uncertain significance ★★ ⚠ same condition
HSPB3 p.Arg23Ter Uncertain significance ★★ same condition
HSPB3 p.Glu106Lys Uncertain significance ★★ ⚠ same condition
HSPB3 p.Leu75Gln Uncertain significance ★★ ⚠ same condition
HSPB3 p.Pro146Leu Uncertain significance ★★ ⚠ same condition
HSPB3 p.Arg116Gln Benign/Likely benign ★★ ⚠ same condition
HSPB3 p.Gly123= Benign ★★ same condition
HSPB3 p.Gly67Ser Benign ★★ 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/hspb3-p-phe80 (accessed [today's date]).

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