Is ALG12 p.Arg166Trp (c.496C>T) pathogenic?

ALG12 p.Arg166Trp (c.496C>T) is classified Uncertain significance in ALG12 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-25). AlphaMissense: likely benign (0.1466); Very rare (popmax 0.00441%, sas); Associated with ALG12-congenital disorder of glycosylation.

What condition is associated with ALG12 p.Arg166Trp (c.496C>T)?

ALG12 p.Arg166Trp (c.496C>T) is associated with ALG12-congenital disorder of glycosylation (ClinVar).

How common is ALG12 p.Arg166Trp (c.496C>T) in the general population?

ALG12 p.Arg166Trp (c.496C>T) is very rare (popmax 0.00441%, 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.Arg166Trp (c.496C>T)?

AlphaMissense predicts likely benign (score 0.1466) — an in-silico prediction, not a clinical call.

ALG12 p.Arg166Trp

c.496C>T · rs375139092 · VCV998963

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1466 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00441%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALG12-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.1466	likely benign
REVEL	0.253	benign-leaning
SaProt	LLR -15.07	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP -2.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 9,924 bp · p 0.17 · regional, not allelic
Overall
CADD	23.4	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 0.00441% South Asian · 4/90,756 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000893%

Overall 0.00118% 19/1,611,346 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00953%	10,495
South Asiangrpmax	0.00441%	22,689
African / African-American	0.004%	24,971
Admixed American	0.00335%	29,859
Remaining individualsnot grpmax-eligible	0.0016%	62,390
European (non-Finnish)	0.000254%	393,079

Finnish 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: ALG12
Protein: p.Arg166Trp
Coding: c.496C>T
MANE Select: NM_024105
dbSNP: rs375139092
Type: single nucleotide variant
Location: chr22:49910062 (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.Arg166Gln 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-arg166trp (accessed [today's date]).

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