Is GALC p.Val607Phe (c.1819G>T) pathogenic?

GALC p.Val607Phe (c.1819G>T) is classified Uncertain significance in GALC (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-19). AlphaMissense: ambiguous (0.4841); Ultra-rare (popmax 0.0287%, amr); Associated with Krabbe disease.

What condition is associated with GALC p.Val607Phe (c.1819G>T)?

GALC p.Val607Phe (c.1819G>T) is associated with Krabbe disease (ClinVar).

How common is GALC p.Val607Phe (c.1819G>T) in the general population?

GALC p.Val607Phe (c.1819G>T) is ultra-rare (popmax 0.0287%, 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.Val607Phe (c.1819G>T)?

AlphaMissense predicts ambiguous (score 0.4841) — an in-silico prediction, not a clinical call.

GALC p.Val607Phe

c.1819G>T · rs929215561 · VCV1415534

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4841 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0287%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Krabbe disease

Computational evidence

Protein change
AlphaMissense	0.4841	ambiguous
REVEL	0.869	moderately pathogenic-leaning
SaProt	LLR -5.58	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.4	GERP 0.27, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 58 kb · p 0.37 · regional, not allelic
Overall
CADD	24.4	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 0.0287% Admixed American · 17/59,210 alleles

Filtering AF 0.0182% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0149%

Overall 0.00188% 30/1,599,746 alleles · ultra-rare exomes 20/1,448,944 · genomes 10/150,802 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0287%	3,483
Remaining individualsnot grpmax-eligible	0.0129%	7,752
African / African-American	0.00269%	37,188
European (non-Finnish)	0.000256%	390,372

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.Val607Phe
Coding: c.1819G>T
MANE Select: NM_000153
dbSNP: rs929215561
Type: single nucleotide variant
Location: chr14:87941410 (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 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
GALC c.1671-1G>A 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-val607phe (accessed [today's date]).

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