Is ALG8 p.Ser443Leu (c.1328C>T) pathogenic?

ALG8 p.Ser443Leu (c.1328C>T) is classified Uncertain significance in ALG8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-15). AlphaMissense: likely benign (0.1252); Ultra-rare (popmax 0.0153%, amr); Associated with Inborn genetic diseases.

What condition is associated with ALG8 p.Ser443Leu (c.1328C>T)?

ALG8 p.Ser443Leu (c.1328C>T) is associated with Inborn genetic diseases, ALG8-congenital disorder of glycosylation (ClinVar).

How common is ALG8 p.Ser443Leu (c.1328C>T) in the general population?

ALG8 p.Ser443Leu (c.1328C>T) is ultra-rare (popmax 0.0153%, amr) (gnomAD).

What do computational predictors say about ALG8 p.Ser443Leu (c.1328C>T)?

AlphaMissense predicts likely benign (score 0.1252) — an in-silico prediction, not a clinical call.

ALG8 p.Ser443Leu

c.1328C>T · rs140716983 · VCV2767209

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1252 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0153%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1252	likely benign
REVEL	0.435	indeterminate
SaProt	LLR -5.29	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 0.075, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 39 kb · p 0.14 · regional, not allelic
Overall
CADD	19.87	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0153% Admixed American · 9/58,710 alleles

Filtering AF 0.00799% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0059%

Overall 0.00509% 76/1,494,298 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0153%	6,523
European (non-Finnish)	0.00586%	17,076
Remaining individualsnot grpmax-eligible	0.00343%	29,127
African / African-American	0.00276%	36,231

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.Ser443Leu
Coding: c.1328C>T
MANE Select: NM_024079
dbSNP: rs140716983
Type: single nucleotide variant
Location: chr11:78104001 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.07
Residue 443: a UniProt-annotated variant site (in pcld3)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ALG8-congenital disorder of glycosylation

Similar variants

ALG8 p.Ser443= Likely benign ★ same residue
ALG8 p.Ser443Ter 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

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-ser443leu (accessed [today's date]).

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