Is HSPB1 p.Pro7Ser (c.19C>T) pathogenic?

HSPB1 p.Pro7Ser (c.19C>T) is classified Conflicting classifications of pathogenicity in HSPB1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-05-11). AlphaMissense: ambiguous (0.4986); Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease axonal type 2F.

What condition is associated with HSPB1 p.Pro7Ser (c.19C>T)?

HSPB1 p.Pro7Ser (c.19C>T) is associated with Charcot-Marie-Tooth disease axonal type 2F, neuronopathy, distal hereditary motor, type 2B (ClinVar).

How common is HSPB1 p.Pro7Ser (c.19C>T) in the general population?

HSPB1 p.Pro7Ser (c.19C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HSPB1 p.Pro7Ser (c.19C>T)?

AlphaMissense predicts ambiguous (score 0.4986) — an in-silico prediction, not a clinical call.

HSPB1 p.Pro7Ser

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.19C>T · rs1563651698 · VCV560407

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4986 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,604,254)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Charcot-Marie-Tooth disease axonal type 2F

Computational evidence

Protein change
AlphaMissense	0.4986	ambiguous
REVEL	0.822	moderately pathogenic-leaning
SaProt	LLR -6.40	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.5, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 1,457 bp · p 0.00055 · regional, not allelic
Overall
CADD	26.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,604,254). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: HSPB1
Protein: p.Pro7Ser
Coding: c.19C>T
MANE Select: NM_001540
dbSNP: rs1563651698
Type: single nucleotide variant
Location: chr7:76302731 (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

Also linked: neuronopathy, distal hereditary motor, type 2B

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.Pro7= Likely benign ★ 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-pro7ser (accessed [today's date]).

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