# NM_000153.4(GALC):c.267G>A (p.Pro89=)

https://sugi.bio/variant/galc-p-pro89

## Summary

**GALC p.Pro89= (c.267G>A)** is classified **Likely benign** in GALC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-01). Ultra-rare (popmax 0.0165%, mid); Associated with Krabbe disease.

**At a glance:** Likely benign · review: Single submitter · rsID rs1258153050 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the GALC gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Krabbe disease.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (United States) |
| Clinical trials | 18 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | GALC is a diagnostic-grade gene on 19 Genomics England panels |

**Commonly reported features of Krabbe disease** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hearing impairment — Very frequent (99-80%)
- Sensorineural hearing impairment — Very frequent (99-80%)
- Visual impairment — Very frequent (99-80%)
- Atypical behavior — Very frequent (99-80%)
- Sensory neuropathy — Very frequent (99-80%)
- Abnormal thumb morphology — Very frequent (99-80%)
- Ataxia — Very frequent (99-80%)
- Spasticity — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006844/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GALC](https://sugi.bio/atlas/gene/GALC/) |
| Protein change (HGVS p.) | p.Pro89= |
| Coding change (HGVS c.) | c.267G>A |
| MANE Select transcript | [NM_000153](https://www.ncbi.nlm.nih.gov/nuccore/NM_000153) |
| dbSNP | [rs1258153050](https://www.ncbi.nlm.nih.gov/snp/rs1258153050/) |
| Variant type | single nucleotide variant |
| Location | chr14:87988205-87988205 (GRCh38) |
| ClinVar | [VCV1638241](https://www.ncbi.nlm.nih.gov/clinvar/variation/1638241/) |

**All HGVS expressions:** `NC_000014.8:g.88454549C>T`, `NC_000014.9:g.87988205C>T`, `NG_011853.3:g.10359G>A`, `NM_000153.4:c.267G>A`, `NM_001201401.2:c.198G>A`, `NM_001201402.2:c.189G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.112, GERP -3.33, phastCons 0.986 — weakly conserved position
- CADD: **PHRED 12.18**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.22 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0165%** (mid) · 1/6,058 in the highest group · 1/1,613,354 alleles overall — ultra-rare (popmax 0.0165%, mid).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**GALC** population constraint: LOEUF 1.019, pLI 3.8591e-15, missense-Z -0.27925. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Krabbe disease** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 94.56, 92% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of GALC (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** GALC's established molecular role includes galactosylceramidase activity.


### Pathways affected {#pathways}

GALC participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Glycosphingolipid catabolism](https://reactome.org/content/detail/R-HSA-9840310) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** galactosylceramidase activity.

**Biological process:** galactosylceramide catabolic process.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-02-01.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-02-01 |

## Associated conditions {#conditions}

[Krabbe disease](https://sugi.bio/atlas/disease/krabbe-disease/).

**Reported phenotype names (ClinVar):** Galactosylceramide beta-galactosidase deficiency, Leukodystrophy, Globoid Cell, Krabbe Disease, GALACTOCEREBROSIDASE DEFICIENCY, GALC DEFICIENCY, GLOBOID CELL LEUKOENCEPHALOPATHY.

## Similar variants {#similar}

Related GALC variant pages (same residue, condition, or type): [GALC p.Pro89Leu](/variant/galc-p-pro89leu), [GALC c.1033+1G>A](/variant/galc-c-1033-plus-1g-a), [GALC c.1034-1G>C](/variant/galc-c-1034-minus-1g-c), [GALC c.1034-2A>G](/variant/galc-c-1034-minus-2a-g), [GALC c.1161+2T>A](/variant/galc-c-1161-plus-2t-a), [GALC c.1251+1G>C](/variant/galc-c-1251-plus-1g-c), [GALC c.1252-1G>C](/variant/galc-c-1252-minus-1g-c), [GALC c.1338+1G>C](/variant/galc-c-1338-plus-1g-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1638241). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*