Is ALG8 p.Ser404Leu (c.1211C>T) pathogenic?

ALG8 p.Ser404Leu (c.1211C>T) is classified Conflicting classifications of pathogenicity in ALG8 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-04). AlphaMissense: likely benign (0.2154); Rare (popmax 0.135%, nfe); Associated with ALG8-congenital disorder of glycosylation.

What condition is associated with ALG8 p.Ser404Leu (c.1211C>T)?

ALG8 p.Ser404Leu (c.1211C>T) is associated with ALG8-congenital disorder of glycosylation (ClinVar).

How common is ALG8 p.Ser404Leu (c.1211C>T) in the general population?

ALG8 p.Ser404Leu (c.1211C>T) is rare (popmax 0.135%, nfe) (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.Ser404Leu (c.1211C>T)?

AlphaMissense predicts likely benign (score 0.2154) — an in-silico prediction, not a clinical call.

ALG8 p.Ser404Leu

c.1211C>T · rs146603801 · VCV306213

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.2154 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.135%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ALG8-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.2154	likely benign
REVEL	0.454	indeterminate
SaProt	LLR -9.76	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.49 · evaluated, not missing
Pangolin	Δ0.20	loss · gain 0.01 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 6.3	GERP 2.1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 39 kb · p 0.14 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.135% European (non-Finnish) · 1,582/1,171,134 alleles

Filtering AF 0.13% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.127%

Overall 0.112% 1,794/1,596,330 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.135%	740
Admixed American	0.105%	954
Remaining individualsnot grpmax-eligible	0.102%	982
Finnishnot grpmax-eligible	0.0922%	1,085
South Asian	0.0217%	4,614
African / African-American	0.0147%	6,801
Ashkenazi Jewishnot grpmax-eligible	0.00343%	29,166

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.Ser404Leu
Coding: c.1211C>T
MANE Select: NM_024079
dbSNP: rs146603801
Type: single nucleotide variant
Location: chr11:78104421 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.07
Residue 404: 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

For ALG8-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Infancy, Neonatal

Similar variants

ALG8 p.Ser404= Likely benign 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-ser404leu (accessed [today's date]).

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