Is ALG8 p.Ser373Pro (c.1117T>C) pathogenic?

ALG8 p.Ser373Pro (c.1117T>C) is classified Uncertain significance in ALG8 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-10-20). AlphaMissense: likely pathogenic (0.8189); Ultra-rare (popmax 0.0217%, amr); Associated with ALG8-congenital disorder of glycosylation.

What condition is associated with ALG8 p.Ser373Pro (c.1117T>C)?

ALG8 p.Ser373Pro (c.1117T>C) is associated with ALG8-congenital disorder of glycosylation, polycystic liver disease 3 with or without kidney cysts (ClinVar).

How common is ALG8 p.Ser373Pro (c.1117T>C) in the general population?

ALG8 p.Ser373Pro (c.1117T>C) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

How is ALG8-CDG inherited?

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

What do computational predictors say about ALG8 p.Ser373Pro (c.1117T>C)?

AlphaMissense predicts likely pathogenic (score 0.8189) — an in-silico prediction, not a clinical call.

ALG8 p.Ser373Pro

c.1117T>C · rs558379335 · VCV387426

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.8189 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALG8-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.8189	likely pathogenic
REVEL	0.814	moderately pathogenic-leaning
SaProt	LLR -15.77	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 3.8	GERP 0.79, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 39 kb · p 0.14 · regional, not allelic
Overall
CADD	24.7	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 0.0217% Admixed American · 13/60,014 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.00235% 38/1,614,160 alleles · ultra-rare exomes 33/1,461,854 · genomes 5/152,306 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0217%	4,616
Remaining individualsnot grpmax-eligible	0.0096%	10,419
African / African-American	0.00266%	37,524
European (non-Finnish)	0.00144%	69,413

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.Ser373Pro
Coding: c.1117T>C
MANE Select: NM_024079
dbSNP: rs558379335
Type: single nucleotide variant
Location: chr11:78106868 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.07
Residue 373: a UniProt-annotated variant site (in pcld3)

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

Disease context

ALG8-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: polycystic liver disease 3 with or without kidney cysts

For ALG8-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Infancy, Neonatal

Similar variants

ALG8 p.Ser373Ala 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.Arg229Ter Pathogenic/Likely pathogenic ★★ same condition
ALG8 p.Arg268Ter 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-ser373pro (accessed [today's date]).

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