Is ALG8 p.Arg41Gln (c.122G>A) pathogenic?

ALG8 p.Arg41Gln (c.122G>A) is classified Pathogenic in ALG8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-08). AlphaMissense: likely pathogenic (0.6674); Very rare (popmax 0.00415%, nfe); Associated with ALG8-congenital disorder of glycosylation.

What condition is associated with ALG8 p.Arg41Gln (c.122G>A)?

ALG8 p.Arg41Gln (c.122G>A) is associated with ALG8-congenital disorder of glycosylation (ClinVar).

How common is ALG8 p.Arg41Gln (c.122G>A) in the general population?

ALG8 p.Arg41Gln (c.122G>A) is very rare (popmax 0.00415%, 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.Arg41Gln (c.122G>A)?

AlphaMissense predicts likely pathogenic (score 0.6674) — an in-silico prediction, not a clinical call.

ALG8 p.Arg41Gln

c.122G>A · rs398124391 · VCV96091

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6674 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00415%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALG8-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.6674	likely pathogenic ✓ concordant with ClinVar
REVEL	0.929	moderately pathogenic-leaning
SaProt	LLR -14.56	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 39 kb · p 0.14 · regional, not allelic
Overall
CADD	33.0	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 0.00415% European (non-Finnish) · 49/1,179,868 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.00359% 58/1,613,450 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,619
European (non-Finnish)grpmax	0.00415%	24,079
Finnishnot grpmax-eligible	0.00314%	31,894
Admixed American	0.00167%	59,956
African / African-American	0.00134%	74,826
South Asian	0.0011%	91,064

Remaining individuals 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.Arg41Gln
Coding: c.122G>A
MANE Select: NM_024079
dbSNP: rs398124391
Type: single nucleotide variant
Location: chr11:78127410 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.07

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.Arg41Ter Pathogenic/Likely pathogenic ★★ 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-arg41gln (accessed [today's date]).

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