Is ALG8 c.478+3A>G pathogenic?

ALG8 c.478+3A>G is classified Uncertain significance in ALG8 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-06-08). Very rare (popmax 0.0022%, sas); Associated with autosomal dominant polycystic liver disease.

What condition is associated with ALG8 c.478+3A>G?

ALG8 c.478+3A>G is associated with autosomal dominant polycystic liver disease (ClinVar).

How common is ALG8 c.478+3A>G in the general population?

ALG8 c.478+3A>G is very rare (popmax 0.0022%, sas) (gnomAD).

ALG8 c.478+3A>G

rs377603174 · VCV2506355

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

autosomal dominant polycystic liver disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
Splice region	donor +3	donor splice region (+3, within the first 6 intronic nt) · inside the BP7-excluded zone
SpliceAI	Δ0.40	donor loss, 3 bp away · masked 0 · deltas
Pangolin	Δ0.71	loss · gain 0.03 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Overall
CADD	21.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/90,962 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000834%

Overall 0.00149% 24/1,606,674 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00321%	31,113
South Asiangrpmax	0.0022%	45,481
European (non-Finnish)	0.00162%	61,770
African / African-American	0.00134%	74,732

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ALG8
Coding: c.478+3A>G
MANE Select: NM_024079
dbSNP: rs377603174
Type: single nucleotide variant
Location: chr11:78121062 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.07

Full ALG8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal dominant polycystic liver disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ALG8 p.Arg229Ter Pathogenic/Likely pathogenic ★★ same condition
ALG8 p.Arg364Ter Pathogenic/Likely pathogenic ★★ same condition
ALG8 p.Gly154Arg Uncertain significance ★★ ⚠ same condition
ALG8 p.Gln54Ter Pathogenic same condition
ALG8 p.Asn91fs Pathogenic/Likely pathogenic ★★ same condition
ALG8 p.Val328fs Pathogenic/Likely pathogenic ★★ same condition
ALG8 p.Ala500_Val501insTer Pathogenic same condition
ALG8 p.Cys124fs 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/alg8-c-478-plus-3a-g (accessed [today's date]).

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