Is HSPB8 p.Lys124= (c.372A>G) pathogenic?

HSPB8 p.Lys124= (c.372A>G) is classified Likely benign in HSPB8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-01). Absent from gnomAD v4.1; Associated with Charcot-Marie-Tooth disease axonal type 2L.

What condition is associated with HSPB8 p.Lys124= (c.372A>G)?

HSPB8 p.Lys124= (c.372A>G) is associated with Charcot-Marie-Tooth disease axonal type 2L (ClinVar).

How common is HSPB8 p.Lys124= (c.372A>G) in the general population?

HSPB8 p.Lys124= (c.372A>G) is absent from gnomAD v4.1 (gnomAD).

HSPB8 p.Lys124=

Q: How is Autosomal dominant Charcot-Marie-Tooth disease type 2L inherited?

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

c.372A>G · rs1954680412 · VCV2033560

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Charcot-Marie-Tooth disease axonal type 2L

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.033	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.37	GERP -5.4, phastCons 0.63
Overall
CADD	4.553	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HSPB8
Protein: p.Lys124=
Coding: c.372A>G
MANE Select: NM_014365
dbSNP: rs1954680412
Type: single nucleotide variant
Location: chr12:119187029 (GRCh38)
Gene constraint: LOEUF 0.944 · pLI 0.05 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.50 · 1 PDB
Residue 124: the shsp domain; a β-strand

Full HSPB8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Charcot-Marie-Tooth disease axonal type 2L — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant Charcot-Marie-Tooth disease type 2L (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult

Similar variants

HSPB8 p.Lys141Glu Pathogenic ★★ same condition
HSPB8 c.-172G>C Uncertain significance ★★ same condition
HSPB8 c.-201G>T Uncertain significance ★★ same condition
HSPB8 c.*123G>A Uncertain significance ★★ same condition
HSPB8 p.Ala46Asp Uncertain significance ★★ ⚠ same condition
HSPB8 p.Ala77Thr Uncertain significance ★★ ⚠ same condition
HSPB8 p.Arg17His Uncertain significance ★★ ⚠ same condition
HSPB8 p.Arg29Cys Uncertain significance ★★ ⚠ 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/hspb8-p-lys124 (accessed [today's date]).

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