Is ALG8 p.Arg229Ter (c.685C>T) pathogenic?

ALG8 p.Arg229Ter (c.685C>T) is classified Pathogenic/Likely pathogenic in ALG8 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-06-10). Very rare (popmax 0.00375%, nfe); Associated with polycystic liver disease 3 with or without kidney cysts.

What condition is associated with ALG8 p.Arg229Ter (c.685C>T)?

ALG8 p.Arg229Ter (c.685C>T) is associated with polycystic liver disease 3 with or without kidney cysts, autosomal dominant polycystic liver disease, ALG8-congenital disorder of glycosylation (ClinVar).

How common is ALG8 p.Arg229Ter (c.685C>T) in the general population?

ALG8 p.Arg229Ter (c.685C>T) is very rare (popmax 0.00375%, nfe) (gnomAD).

ALG8 p.Arg229Ter

c.685C>T · rs533704173 · VCV1328207

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00375%, nfe)

Conditions

polycystic liver disease 3 with or without kidney cysts

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 13
Splicing
SpliceAI	Δ0.27	acceptor loss · deltas
Pangolin	Δ0.41	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.1	GERP 2.1, phastCons 1
Overall
CADD	52.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00375% European (non-Finnish) · 44/1,173,912 alleles

Filtering AF 0.00284% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00253%

Overall 0.00287% 46/1,601,470 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00375%	26,680
Remaining individualsnot grpmax-eligible	0.00161%	62,138
South Asian	0.00113%	88,744

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
Protein: p.Arg229Ter
Coding: c.685C>T
MANE Select: NM_024079
dbSNP: rs533704173
Type: single nucleotide variant
Location: chr11:78113978 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.07
Residue 229: a UniProt-annotated variant site (in pcld3)

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

Disease context

polycystic liver disease 3 with or without kidney cysts — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant polycystic liver disease ALG8-congenital disorder of glycosylation

Similar variants

ALG8 p.Arg229Gln Uncertain significance ★ ⚠ same residue
ALG8 c.368+2T>G Likely pathogenic ★★ same condition
ALG8 c.674-2A>G Likely pathogenic ★★ same condition
ALG8 c.777+1G>A Likely pathogenic ★★ same condition
ALG8 c.95+1G>A Likely pathogenic ★★ same condition
ALG8 p.Arg179Ter Pathogenic/Likely pathogenic ★★ same condition
ALG8 p.Arg268Ter Pathogenic/Likely pathogenic ★★ same condition
ALG8 p.Arg364Ter 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/alg8-p-arg229ter (accessed [today's date]).

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