Is GALC p.Ala372Ser (c.1114G>T) pathogenic?

GALC p.Ala372Ser (c.1114G>T) is classified Uncertain significance in GALC (ClinVar, Multiple submitters, 11 submitters; last evaluated 2024-11-17). AlphaMissense: likely benign (0.1373); Rare (popmax 0.164%, mid); Associated with Krabbe disease.

What condition is associated with GALC p.Ala372Ser (c.1114G>T)?

GALC p.Ala372Ser (c.1114G>T) is associated with Krabbe disease (ClinVar).

How common is GALC p.Ala372Ser (c.1114G>T) in the general population?

GALC p.Ala372Ser (c.1114G>T) is rare (popmax 0.164%, mid) (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.Ala372Ser (c.1114G>T)?

AlphaMissense predicts likely benign (score 0.1373) — an in-silico prediction, not a clinical call.

GALC p.Ala372Ser

c.1114G>T · rs759286485 · VCV885479

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.1373 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Krabbe disease

Computational evidence

Protein change
AlphaMissense	0.1373	likely benign
REVEL	0.625	indeterminate
SaProt	LLR -5.55	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 58 kb · p 0.37 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.164% Middle Eastern · 10/6,080 alleles

Filtering AF 0.0891% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0679%

Overall 0.00483% 78/1,613,334 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.164%	608
South Asian	0.00988%	10,120
Remaining individualsnot grpmax-eligible	0.0064%	15,616
European (non-Finnish)	0.00432%	23,127
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,580
Admixed American	0.00333%	29,990
African / African-American	0.00134%	74,886

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.Ala372Ser
Coding: c.1114G>T
MANE Select: NM_000153
dbSNP: rs759286485
Type: single nucleotide variant
Location: chr14:87963431 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.56
Residue 372: a disulfide bond

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.Ala372Thr Uncertain significance ★★ ⚠ 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-ala372ser (accessed [today's date]).

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