Is GALC p.Pro481Ser (c.1441C>T) pathogenic?

GALC p.Pro481Ser (c.1441C>T) is classified Uncertain significance in GALC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-10). AlphaMissense: likely benign (0.1517); Ultra-rare (popmax 0.0134%, amr); Associated with Krabbe disease.

What condition is associated with GALC p.Pro481Ser (c.1441C>T)?

GALC p.Pro481Ser (c.1441C>T) is associated with Krabbe disease (ClinVar).

How common is GALC p.Pro481Ser (c.1441C>T) in the general population?

GALC p.Pro481Ser (c.1441C>T) is ultra-rare (popmax 0.0134%, amr) (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.Pro481Ser (c.1441C>T)?

AlphaMissense predicts likely benign (score 0.1517) — an in-silico prediction, not a clinical call.

GALC p.Pro481Ser

c.1441C>T · rs759122249 · VCV972103

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1517 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Krabbe disease

Computational evidence

Protein change
AlphaMissense	0.1517	likely benign
REVEL	0.73	pathogenic-leaning
SaProt	LLR -4.99	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 58 kb · p 0.37 · regional, not allelic
Overall
CADD	24.6	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 0.0134% Admixed American · 8/59,884 alleles

Filtering AF 0.00663% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.000682% 11/1,612,868 alleles · ultra-rare exomes 9/1,460,900 · genomes 2/151,968 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0134%	7,485
Remaining individualsnot grpmax-eligible	0.0032%	31,204
African / African-American	0.00134%	74,780

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.Pro481Ser
Coding: c.1441C>T
MANE Select: NM_000153
dbSNP: rs759122249
Type: single nucleotide variant
Location: chr14:87947776 (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.Pro481= Conflicting classifications of pathogenicity ★ 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
GALC c.1252-1G>C Pathogenic/Likely pathogenic ★★ same condition
GALC c.1338+1G>C 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-pro481ser (accessed [today's date]).

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