Is GALC p.Arg531Pro (c.1592G>C) pathogenic?

GALC p.Arg531Pro (c.1592G>C) is classified Conflicting classifications of pathogenicity in GALC (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-03). AlphaMissense: likely pathogenic (0.9959); Absent from gnomAD v4.1; Associated with Krabbe disease.

What condition is associated with GALC p.Arg531Pro (c.1592G>C)?

GALC p.Arg531Pro (c.1592G>C) is associated with Krabbe disease (ClinVar).

How common is GALC p.Arg531Pro (c.1592G>C) in the general population?

GALC p.Arg531Pro (c.1592G>C) is absent from gnomAD v4.1 (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.Arg531Pro (c.1592G>C)?

AlphaMissense predicts likely pathogenic (score 0.9959) — an in-silico prediction, not a clinical call.

GALC p.Arg531Pro

c.1592G>C · rs200378205 · VCV623356

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9959 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Krabbe disease

Computational evidence

Protein change
AlphaMissense	0.9959	likely pathogenic · top 1% in GALC
REVEL	0.905	moderately pathogenic-leaning
SaProt	LLR -15.24	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 58 kb · p 0.37 · regional, not allelic
Overall
CADD	27.9	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

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: GALC
Protein: p.Arg531Pro
Coding: c.1592G>C
MANE Select: NM_000153
dbSNP: rs200378205
Type: single nucleotide variant
Location: chr14:87945631 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.56
Residue 531: a UniProt-annotated variant site (in krb); a UniProt-annotated variant site (in krb; infantile; significant reduction of activity)

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.Arg531Cys Pathogenic/Likely pathogenic ★★ same residue
GALC p.Arg531His Pathogenic/Likely pathogenic ★★ ⚠ same residue
GALC p.Arg531Leu Likely 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
GALC c.1251+1G>C 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/galc-p-arg531pro (accessed [today's date]).

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