Is ALG8 p.Asp225= (c.675T>C) pathogenic?

ALG8 p.Asp225= (c.675T>C) is classified Conflicting classifications of pathogenicity in ALG8 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-13). Rare (popmax 0.241%, nfe); Associated with ALG8-congenital disorder of glycosylation.

What condition is associated with ALG8 p.Asp225= (c.675T>C)?

ALG8 p.Asp225= (c.675T>C) is associated with ALG8-congenital disorder of glycosylation (ClinVar).

How common is ALG8 p.Asp225= (c.675T>C) in the general population?

ALG8 p.Asp225= (c.675T>C) is rare (popmax 0.241%, nfe) (gnomAD).

How is ALG8-CDG inherited?

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

ALG8 p.Asp225=

c.675T>C · rs139106381 · VCV306220

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.241%, nfe)

Conditions

ALG8-congenital disorder of glycosylation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.084	moderately benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.37 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4	GERP 2.1, phastCons 1
Overall
CADD	14.01	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.241% European (non-Finnish) · 2,828/1,171,606 alleles

Filtering AF 0.234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.231%

Overall 0.187% 2,992/1,598,082 alleles · rare exomes 2,793/1,445,892 · genomes 199/152,190 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.32%	76
European (non-Finnish)grpmax	0.241%	414
Remaining individualsnot grpmax-eligible	0.135%	738
Admixed American	0.0453%	2,208
African / African-American	0.0335%	2,985
Finnishnot grpmax-eligible	0.019%	5,269
Middle Eastern	0.0165%	6,066
South Asian	0.00452%	22,101

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp225=
Coding: c.675T>C
MANE Select: NM_024079
dbSNP: rs139106381
Type: single nucleotide variant
Location: chr11:78113988 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.07
Residue 225: 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 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
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-asp225 (accessed [today's date]).

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