Is ALG12 p.Val408= (c.1224C>A) pathogenic?

ALG12 p.Val408= (c.1224C>A) is classified Likely benign in ALG12 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-26). Very rare (popmax 0.00667%, afr); Associated with ALG12-congenital disorder of glycosylation.

What condition is associated with ALG12 p.Val408= (c.1224C>A)?

ALG12 p.Val408= (c.1224C>A) is associated with ALG12-congenital disorder of glycosylation (ClinVar).

How common is ALG12 p.Val408= (c.1224C>A) in the general population?

ALG12 p.Val408= (c.1224C>A) is very rare (popmax 0.00667%, afr) (gnomAD).

How is ALG12-CDG inherited?

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

ALG12 p.Val408=

c.1224C>A · rs146341718 · VCV1658054

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Conditions

ALG12-congenital disorder of glycosylation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
REVEL	0.043	moderately benign-leaning
Splicing
SpliceAI	Δ0.20	donor gain · deltas
Pangolin	Δ0.22	loss · gain 0.12 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 4.1	GERP 0.35, phastCons 1
Overall
CADD	15.22	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% African / African-American · 5/74,926 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00031% 5/1,614,078 alleles · very rare exomes 4/1,461,874 · genomes 1/152,204 · joint denominator

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.Val408=
Coding: c.1224C>A
MANE Select: NM_024105
dbSNP: rs146341718
Type: single nucleotide variant
Location: chr22:49904193 (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 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
ALG12 c.470-3C>T 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-val408 (accessed [today's date]).

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