Is ALG12 p.Val454= (c.1362C>T) pathogenic?

ALG12 p.Val454= (c.1362C>T) is classified Conflicting classifications of pathogenicity in ALG12 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-26). Low-frequency (popmax 1.74%, eas); Associated with ALG12-congenital disorder of glycosylation.

What condition is associated with ALG12 p.Val454= (c.1362C>T)?

ALG12 p.Val454= (c.1362C>T) is associated with ALG12-congenital disorder of glycosylation (ClinVar).

How common is ALG12 p.Val454= (c.1362C>T) in the general population?

ALG12 p.Val454= (c.1362C>T) is low-frequency (popmax 1.74%, eas) (gnomAD).

How is ALG12-CDG inherited?

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

ALG12 p.Val454=

c.1362C>T · rs12163163 · VCV342042

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.74%, eas)

Conditions

ALG12-congenital disorder of glycosylation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.096	moderately benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.4	GERP -3.2
Overall
CADD	1.747	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.74% East Asian · 782/44,882 alleles

Filtering AF 1.64% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.6%

Overall 0.103% 1,662/1,614,206 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	1.74%	57
European (non-Finnish)	0.0663%	1,509
Remaining individualsnot grpmax-eligible	0.0576%	1,736
South Asian	0.0439%	2,277
Admixed American	0.0167%	6,003
African / African-American	0.00799%	12,510
Finnishnot grpmax-eligible	0.00781%	12,809
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

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.Val454=
Coding: c.1362C>T
MANE Select: NM_024105
dbSNP: rs12163163
Type: single nucleotide variant
Location: chr22:49903943 (GRCh38)
Gene constraint: LOEUF 0.965 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.26
Residue 454: 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.Val454Ile Conflicting classifications of pathogenicity ★ ⚠ 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-val454 (accessed [today's date]).

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