Is ALG9 p.Trp565Ter (c.1695G>A) pathogenic?

ALG9 p.Trp565Ter (c.1695G>A) is classified Conflicting classifications of pathogenicity in ALG9 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-01). Very rare (popmax 0.000254%, nfe); Associated with familial cystic renal disease.

What condition is associated with ALG9 p.Trp565Ter (c.1695G>A)?

ALG9 p.Trp565Ter (c.1695G>A) is associated with familial cystic renal disease (ClinVar).

How common is ALG9 p.Trp565Ter (c.1695G>A) in the general population?

ALG9 p.Trp565Ter (c.1695G>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

ALG9 p.Trp565Ter

c.1695G>A · VCV3906840

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

familial cystic renal disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (14 of 15, 38 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
REVEL	0.471	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Overall
CADD	39.0	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 0.000254% European (non-Finnish) · 3/1,180,002 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,826 alleles · very rare

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: ALG9
Protein: p.Trp565Ter
Coding: c.1695G>A
MANE Select: NM_024740
Type: single nucleotide variant
Location: chr11:111809681 (GRCh38)
Gene constraint: LOEUF 0.853 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.35 · 2 PDB

Full ALG9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial cystic renal disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ALG9 p.Arg112Cys Uncertain significance ★★ ⚠ same condition
ALG9 c.896_1602del Pathogenic ★ same condition
ALG9 c.566-1G>A Pathogenic/Likely pathogenic ★★ same type
ALG9 c.896-2A>G Likely pathogenic ★★ same type
ALG9 p.Arg143Ter Pathogenic/Likely pathogenic ★★ same type
ALG9 p.Trp248Ter Pathogenic/Likely pathogenic ★★ same type
ALG9 p.Tyr287Cys Pathogenic/Likely pathogenic ★★ same type
ALG9 c.*1607C>T Uncertain significance ★★ same type

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/alg9-p-trp565ter (accessed [today's date]).

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