Is ALG3 p.Arg229Cys (c.685C>T) pathogenic?

ALG3 p.Arg229Cys (c.685C>T) is classified Uncertain significance in ALG3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-14). AlphaMissense: likely benign (0.0906); Rare (popmax 0.115%, mid); Associated with Inborn genetic diseases.

What condition is associated with ALG3 p.Arg229Cys (c.685C>T)?

ALG3 p.Arg229Cys (c.685C>T) is associated with Inborn genetic diseases, ALG3-congenital disorder of glycosylation (ClinVar).

How common is ALG3 p.Arg229Cys (c.685C>T) in the general population?

ALG3 p.Arg229Cys (c.685C>T) is rare (popmax 0.115%, mid) (gnomAD).

What do computational predictors say about ALG3 p.Arg229Cys (c.685C>T)?

AlphaMissense predicts likely benign (score 0.0906) — an in-silico prediction, not a clinical call.

ALG3 p.Arg229Cys

c.685C>T · rs537211234 · VCV1957110

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0906 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.115%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0906	likely benign
REVEL	0.448	indeterminate
SaProt	LLR -5.83	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 5.9	GERP 0.63, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 2,165 bp · p 0.0031 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.115% Middle Eastern · 7/6,080 alleles

Filtering AF 0.054% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0383%

Overall 0.00528% 85/1,610,718 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.115%	869
Admixed American	0.0252%	3,968
European (non-Finnish)	0.00484%	20,679
Remaining individualsnot grpmax-eligible	0.00481%	20,791
East Asian	0.00223%	44,806
South Asian	0.00222%	45,087

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.Arg229Cys
Coding: c.685C>T
MANE Select: NM_005787
dbSNP: rs537211234
Type: single nucleotide variant
Location: chr3:184244642 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ALG3-congenital disorder of glycosylation

Similar variants

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.Arg354Cys Likely pathogenic ★★ same condition
ALG3 p.Arg354His Pathogenic/Likely 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-arg229cys (accessed [today's date]).

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