Is GALK1 p.Arg287Cys (c.859C>T) pathogenic?

GALK1 p.Arg287Cys (c.859C>T) is classified Uncertain significance in GALK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-20). AlphaMissense: likely pathogenic (0.7601); Very rare (popmax 0.00225%, sas); Associated with galactokinase deficiency.

What condition is associated with GALK1 p.Arg287Cys (c.859C>T)?

GALK1 p.Arg287Cys (c.859C>T) is associated with galactokinase deficiency (ClinVar).

How common is GALK1 p.Arg287Cys (c.859C>T) in the general population?

GALK1 p.Arg287Cys (c.859C>T) is very rare (popmax 0.00225%, sas) (gnomAD).

How is Galactokinase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about GALK1 p.Arg287Cys (c.859C>T)?

AlphaMissense predicts likely pathogenic (score 0.7601) — an in-silico prediction, not a clinical call.

GALK1 p.Arg287Cys

c.859C>T · rs771667085 · VCV2166941

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7601 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00225%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

galactokinase deficiency

Computational evidence

Protein change
AlphaMissense	0.7601	likely pathogenic
REVEL	0.749	pathogenic-leaning
SaProt	LLR -13.75	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 6.3	phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 7,077 bp · p 0.22 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00225% South Asian · 2/88,762 alleles

Filtering AF 0.000374% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00014%

Overall 0.000314% 5/1,593,008 alleles · very rare exomes 4/1,440,826 · genomes 1/152,182 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00225%	44,381
Admixed American	0.00171%	58,438
European (non-Finnish)	0.00017%	587,265

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: GALK1
Protein: p.Arg287Cys
Coding: c.859C>T
MANE Select: NM_000154
dbSNP: rs771667085
Type: single nucleotide variant
Location: chr17:75758534 (GRCh38)
Gene constraint: LOEUF 1.198 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 97.31 · 20 PDB
Residue 287: an α-helix

Full GALK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

galactokinase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Galactokinase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

GALK1 p.Arg287fs Pathogenic ★ same residue
GALK1 p.Arg287His Uncertain significance ★ ⚠ same residue
GALK1 c.355+1G>A Likely pathogenic ★★ same condition
GALK1 c.611+1G>T Pathogenic/Likely pathogenic ★★ same condition
GALK1 c.793+1G>T Pathogenic/Likely pathogenic ★★ same condition
GALK1 c.793+2T>C Pathogenic/Likely pathogenic ★★ same condition
GALK1 c.793+2T>G Pathogenic/Likely pathogenic ★★ same condition
GALK1 p.Arg256Trp 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/galk1-p-arg287cys (accessed [today's date]).

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