Is ALG12 p.Tyr414Ter (c.1242C>G) pathogenic?

ALG12 p.Tyr414Ter (c.1242C>G) is classified Pathogenic in ALG12 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2002-10-01). Absent from gnomAD v4.1; Associated with ALG12-congenital disorder of glycosylation.

What condition is associated with ALG12 p.Tyr414Ter (c.1242C>G)?

ALG12 p.Tyr414Ter (c.1242C>G) is associated with ALG12-congenital disorder of glycosylation (ClinVar).

How common is ALG12 p.Tyr414Ter (c.1242C>G) in the general population?

ALG12 p.Tyr414Ter (c.1242C>G) is absent from gnomAD v4.1 (gnomAD).

How is ALG12-CDG inherited?

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

ALG12 p.Tyr414Ter

c.1242C>G · rs121907935 · VCV3438

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

ALG12-congenital disorder of glycosylation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (10 of 10) — the truncated protein is likely expressed. PVS1 input, not an applied code
REVEL	0.424	indeterminate
Splicing
SpliceAI	Δ0.21	acceptor gain · deltas
Pangolin	Δ0.33	loss · gain 0.08 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP -4.6	GERP -3.2
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ALG12
Protein: p.Tyr414Ter
Coding: c.1242C>G
MANE Select: NM_024105
dbSNP: rs121907935
Type: single nucleotide variant
Location: chr22:49904063 (GRCh38)
Gene constraint: LOEUF 0.965 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.26
Residue 414: a UniProt-annotated variant site (in cdg1g)

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.Tyr414= 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-tyr414ter (accessed [today's date]).

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