Is ALG3 p.Arg354Cys (c.1060C>T) pathogenic?

ALG3 p.Arg354Cys (c.1060C>T) is classified Likely pathogenic in ALG3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-02). AlphaMissense: likely pathogenic (0.8306); Very rare (popmax 0.00339%, nfe); Associated with ALG3-congenital disorder of glycosylation.

What condition is associated with ALG3 p.Arg354Cys (c.1060C>T)?

ALG3 p.Arg354Cys (c.1060C>T) is associated with ALG3-congenital disorder of glycosylation (ClinVar).

How common is ALG3 p.Arg354Cys (c.1060C>T) in the general population?

ALG3 p.Arg354Cys (c.1060C>T) is very rare (popmax 0.00339%, nfe) (gnomAD).

How is ALG3-CDG inherited?

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

What do computational predictors say about ALG3 p.Arg354Cys (c.1060C>T)?

AlphaMissense predicts likely pathogenic (score 0.8306) — an in-silico prediction, not a clinical call.

ALG3 p.Arg354Cys

c.1060C>T · rs762510540 · VCV2734602

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8306 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00339%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALG3-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.8306	likely pathogenic ✓ concordant with ClinVar
REVEL	0.921	moderately pathogenic-leaning
SaProt	LLR -14.38	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.79 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 2,165 bp · p 0.0031 · 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 0.00339% European (non-Finnish) · 40/1,179,894 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00266% 43/1,613,734 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00339%	29,497
Finnishnot grpmax-eligible	0.00157%	63,846
African / African-American	0.00133%	74,936
South Asian	0.0011%	91,090

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: ALG3
Protein: p.Arg354Cys
Coding: c.1060C>T
MANE Select: NM_005787
dbSNP: rs762510540
Type: single nucleotide variant
Location: chr3:184242907 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.05

Full ALG3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ALG3-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For ALG3-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ALG3 p.Arg354His Pathogenic/Likely pathogenic ★★ same residue
ALG3 p.Arg354Ser Uncertain significance ★ ⚠ same residue
ALG3 c.444+1G>T Likely pathogenic ★★ same condition
ALG3 p.Arg171Gln Pathogenic/Likely pathogenic ★★ same condition
ALG3 p.Arg266Cys Pathogenic ★★ same condition
ALG3 p.Asn174Ser Likely pathogenic ★★ ⚠ same condition
ALG3 p.Gly55= Pathogenic/Likely pathogenic ★★ same condition
ALG3 p.Ile69Thr 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/alg3-p-arg354cys (accessed [today's date]).

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