Is ALG8 p.Leu253Ser (c.758T>C) pathogenic?

ALG8 p.Leu253Ser (c.758T>C) is classified Uncertain significance in ALG8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-22). AlphaMissense: likely pathogenic (0.5832); Absent from gnomAD v4.1; Associated with polycystic liver disease 3 with or without kidney cysts.

What condition is associated with ALG8 p.Leu253Ser (c.758T>C)?

ALG8 p.Leu253Ser (c.758T>C) is associated with polycystic liver disease 3 with or without kidney cysts (ClinVar).

How common is ALG8 p.Leu253Ser (c.758T>C) in the general population?

ALG8 p.Leu253Ser (c.758T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ALG8 p.Leu253Ser (c.758T>C)?

AlphaMissense predicts likely pathogenic (score 0.5832) — an in-silico prediction, not a clinical call.

ALG8 p.Leu253Ser

c.758T>C · rs2136902870 · VCV1526064

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5832 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

polycystic liver disease 3 with or without kidney cysts

Computational evidence

Protein change
AlphaMissense	0.5832	likely pathogenic
REVEL	0.759	pathogenic-leaning
SaProt	LLR -12.32	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 39 kb · p 0.14 · regional, not allelic
Overall
CADD	27.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ALG8
Protein: p.Leu253Ser
Coding: c.758T>C
MANE Select: NM_024079
dbSNP: rs2136902870
Type: single nucleotide variant
Location: chr11:78113905 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.07
Residue 253: 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

Similar variants

ALG8 p.Leu253Met Uncertain significance ★ ⚠ same residue
ALG8 p.Leu253= Likely benign ★★ same residue
ALG8 p.Leu253Val Uncertain significance ★ ⚠ same residue
ALG8 c.368+2T>G Likely pathogenic ★★ same condition
ALG8 c.674-2A>G Likely pathogenic ★★ same condition
ALG8 c.95+1G>A Likely pathogenic ★★ same condition
ALG8 p.Arg179Ter Pathogenic/Likely pathogenic ★★ same condition
ALG8 p.Arg229Ter 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-leu253ser (accessed [today's date]).

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