Is CSTB p.His58= (c.174C>T) pathogenic?

CSTB p.His58= (c.174C>T) is classified Likely benign in CSTB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-10-16). Very rare (popmax 0.00445%, eas); Associated with progressive myoclonus epilepsy.

What condition is associated with CSTB p.His58= (c.174C>T)?

CSTB p.His58= (c.174C>T) is associated with progressive myoclonus epilepsy (ClinVar).

How common is CSTB p.His58= (c.174C>T) in the general population?

CSTB p.His58= (c.174C>T) is very rare (popmax 0.00445%, eas) (gnomAD).

CSTB p.His58=

c.174C>T · rs763095750 · VCV507395

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Conditions

progressive myoclonus epilepsy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.83 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.6	GERP -4.1
Overall
CADD	0.798	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00445% East Asian · 2/44,904 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000929% 15/1,614,060 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,452
Admixed American	0.00333%	30,007
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.000847%	118,006

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: CSTB
Protein: p.His58=
Coding: c.174C>T
MANE Select: NM_000100
dbSNP: rs763095750
Type: single nucleotide variant
Location: chr21:43774325 (GRCh38)
Gene constraint: LOEUF 1.681 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 95.81 · 3 PDB
Residue 58: a β-strand

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

Disease context

progressive myoclonus epilepsy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CSTB p.His58Tyr Uncertain significance ★★ ⚠ same residue
CSTB c.67-1G>C Pathogenic ★★ same condition
CSTB p.Arg68Ter Pathogenic ★★ same condition
CSTB p.Gln22Ter Pathogenic/Likely pathogenic ★★ same condition
CSTB p.Gln46Ter Pathogenic/Likely pathogenic ★★ same condition
CSTB p.Ala49Thr Uncertain significance ★★ same condition
CSTB p.Ala90Thr Uncertain significance ★★ ⚠ same condition
CSTB p.Asn52Ile 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/cstb-p-his58 (accessed [today's date]).

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