Is GALC p.Ser94fs (c.281del) pathogenic?

GALC p.Ser94fs (c.281del) is classified Pathogenic in GALC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-30). Very rare (popmax 0.000593%, nfe); Associated with Krabbe disease.

What condition is associated with GALC p.Ser94fs (c.281del)?

GALC p.Ser94fs (c.281del) is associated with Krabbe disease (ClinVar).

How common is GALC p.Ser94fs (c.281del) in the general population?

GALC p.Ser94fs (c.281del) is very rare (popmax 0.000593%, nfe) (gnomAD).

How is Krabbe disease inherited?

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

GALC p.Ser94fs

c.281del · rs2139758786 · VCV1454136

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Conditions

Krabbe disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.7	GERP -0.94, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000593% European (non-Finnish) · 7/1,179,854 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000479% 7/1,461,468 alleles · very rare

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: GALC
Protein: p.Ser94fs
Coding: c.281del
MANE Select: NM_000153
dbSNP: rs2139758786
Type: Deletion
Location: chr14:87988191 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.56

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

Disease context

Krabbe disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Krabbe disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

GALC p.Ser94Pro Uncertain significance ★ ⚠ same residue
GALC c.1488_1489+2del Pathogenic/Likely pathogenic ★★ same condition
GALC p.Ala579fs Pathogenic ★★ same condition
GALC p.Ala618fs Pathogenic/Likely pathogenic ★★ same condition
GALC p.Asn167fs Pathogenic ★★ same condition
GALC p.Glu338fs Pathogenic ★★ same condition
GALC p.Gly52fs Pathogenic/Likely pathogenic ★★ same condition
GALC p.Gly59fs 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/galc-p-ser94fs (accessed [today's date]).

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