Is GALC p.Arg290Ser (c.868C>A) pathogenic?

GALC p.Arg290Ser (c.868C>A) is classified Likely pathogenic in GALC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-15). AlphaMissense: likely pathogenic (0.9748); Very rare (popmax 8.48e-05%, nfe); Associated with Krabbe disease.

What condition is associated with GALC p.Arg290Ser (c.868C>A)?

GALC p.Arg290Ser (c.868C>A) is associated with Krabbe disease (ClinVar).

How common is GALC p.Arg290Ser (c.868C>A) in the general population?

GALC p.Arg290Ser (c.868C>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Krabbe disease inherited?

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

What do computational predictors say about GALC p.Arg290Ser (c.868C>A)?

AlphaMissense predicts likely pathogenic (score 0.9748) — an in-silico prediction, not a clinical call.

GALC p.Arg290Ser

c.868C>A · rs780750448 · VCV2112804

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9748 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Krabbe disease

Computational evidence

Protein change
AlphaMissense	0.9748	likely pathogenic ✓ concordant with ClinVar · top 3% in GALC
REVEL	0.952	strongly pathogenic-leaning
SaProt	LLR -9.77	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 58 kb · p 0.37 · regional, not allelic
Overall
CADD	29.0	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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,582 alleles

Overall 6.2e-05% 1/1,613,018 alleles · very rare exomes 0/1,461,274 · genomes 1/151,744 · joint denominator

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.Arg290Ser
Coding: c.868C>A
MANE Select: NM_000153
dbSNP: rs780750448
Type: single nucleotide variant
Location: chr14:87968375 (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.Arg290Cys Pathogenic/Likely pathogenic ★★ same residue
GALC p.Arg290His Conflicting classifications of pathogenicity ★ ⚠ same residue
GALC p.Arg290= Likely benign ★ same residue
GALC p.Arg290fs Pathogenic ★ same residue
GALC c.1033+1G>A Likely pathogenic ★★ same condition
GALC c.1034-1G>C Pathogenic/Likely pathogenic ★★ same condition
GALC c.1034-2A>G Pathogenic/Likely pathogenic ★★ same condition
GALC c.1161+2T>A 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/galc-p-arg290ser (accessed [today's date]).

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