Is ALG8 p.Ala506Thr (c.1516G>A) pathogenic?

ALG8 p.Ala506Thr (c.1516G>A) is classified Conflicting classifications of pathogenicity in ALG8 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-06-12). AlphaMissense: likely benign (0.1063); Rare (popmax 0.28%, mid); Associated with ALG8-congenital disorder of glycosylation.

What condition is associated with ALG8 p.Ala506Thr (c.1516G>A)?

ALG8 p.Ala506Thr (c.1516G>A) is associated with ALG8-congenital disorder of glycosylation (ClinVar).

How common is ALG8 p.Ala506Thr (c.1516G>A) in the general population?

ALG8 p.Ala506Thr (c.1516G>A) is rare (popmax 0.28%, mid) (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.Ala506Thr (c.1516G>A)?

AlphaMissense predicts likely benign (score 0.1063) — an in-silico prediction, not a clinical call.

ALG8 p.Ala506Thr

c.1516G>A · rs149692072 · VCV882709

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1063 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.28%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ALG8-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.1063	likely benign
REVEL	0.482	indeterminate
SaProt	LLR -8.70	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 3.3	GERP 1.2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 39 kb · p 0.14 · regional, not allelic
Overall
CADD	19.49	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 0.28% Middle Eastern · 17/6,062 alleles

Filtering AF 0.179% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.154%

Overall 0.0208% 335/1,614,190 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.28%	357
South Asian	0.186%	539
Admixed American	0.0416%	2,401
Remaining individualsnot grpmax-eligible	0.0352%	2,841
European (non-Finnish)	0.00839%	11,920
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
East Asian	0.00223%	44,884
African / African-American	0.00133%	75,046

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.Ala506Thr
Coding: c.1516G>A
MANE Select: NM_024079
dbSNP: rs149692072
Type: single nucleotide variant
Location: chr11:78101029 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.07
Residue 506: 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

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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
ALG8 p.Arg364Ter 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-ala506thr (accessed [today's date]).

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