Is ALG12 p.Arg211Cys (c.631C>T) pathogenic?

ALG12 p.Arg211Cys (c.631C>T) is classified Benign/Likely benign in ALG12 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-29). AlphaMissense: likely benign (0.1029); Low-frequency (popmax 3.09%, sas); Associated with ALG12-congenital disorder of glycosylation.

What condition is associated with ALG12 p.Arg211Cys (c.631C>T)?

ALG12 p.Arg211Cys (c.631C>T) is associated with ALG12-congenital disorder of glycosylation (ClinVar).

How common is ALG12 p.Arg211Cys (c.631C>T) in the general population?

ALG12 p.Arg211Cys (c.631C>T) is low-frequency (popmax 3.09%, sas) (gnomAD).

How is ALG12-CDG inherited?

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

What do computational predictors say about ALG12 p.Arg211Cys (c.631C>T)?

AlphaMissense predicts likely benign (score 0.1029) — an in-silico prediction, not a clinical call.

ALG12 p.Arg211Cys

c.631C>T · rs144665682 · VCV96097

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1029 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.09%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALG12-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.1029	likely benign
REVEL	0.237	benign-leaning
SaProt	LLR -7.70	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.55	GERP -3.1
Regional constraint	o/e 0.95	unconstrained · MANE · 9,924 bp · p 0.17 · regional, not allelic
Overall
CADD	14.58	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 3.09% South Asian · 2,819/91,084 alleles

Filtering AF 3% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.96%

Overall 0.68% 10,975/1,614,130 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	3.09%	32
East Asian	3.02%	33
Middle Eastern	0.841%	119
Remaining individualsnot grpmax-eligible	0.762%	131
African / African-American	0.601%	166
Ashkenazi Jewishnot grpmax-eligible	0.5%	200
European (non-Finnish)	0.46%	218
Admixed American	0.223%	448
Finnishnot grpmax-eligible	0.181%	551

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: ALG12
Protein: p.Arg211Cys
Coding: c.631C>T
MANE Select: NM_024105
dbSNP: rs144665682
Type: single nucleotide variant
Location: chr22:49909927 (GRCh38)
Gene constraint: LOEUF 0.965 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.26

Full ALG12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ALG12-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For ALG12-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ALG12 p.Arg211= Likely benign ★ same residue
ALG12 c.295+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALG12 c.768+1G>A Likely pathogenic ★★ same condition
ALG12 p.Arg146Gln Pathogenic/Likely pathogenic ★★ same condition
ALG12 p.Arg202Ter Pathogenic/Likely pathogenic ★★ same condition
ALG12 p.Gly101Arg Likely pathogenic ★★ same condition
ALG12 p.Thr67Met Pathogenic/Likely pathogenic ★★ same condition
ALG12 c.469+5G>A Uncertain significance ★★ 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/alg12-p-arg211cys (accessed [today's date]).

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