Is ALG12 p.Val33= (c.99G>A) pathogenic?

ALG12 p.Val33= (c.99G>A) is classified Benign in ALG12 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). Common (popmax 12.2%, afr) — too common for a highly-penetrant pathogenic allele; Associated with ALG12-congenital disorder of glycosylation.

What condition is associated with ALG12 p.Val33= (c.99G>A)?

ALG12 p.Val33= (c.99G>A) is associated with ALG12-congenital disorder of glycosylation (ClinVar).

How is ALG12-CDG inherited?

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

ALG12 p.Val33=

Q: How common is ALG12 p.Val33= (c.99G>A) in the general population?

ALG12 p.Val33= (c.99G>A) is common (popmax 12.2%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.99G>A · rs76707654 · VCV342060

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 12.2%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

ALG12-congenital disorder of glycosylation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.18	GERP -2.8, phastCons 0.97
Overall
CADD	8.129	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 12.2% African / African-American · 9,131/75,034 alleles

Filtering AF 12% ClinGen BA1/BS1 input FAF95, joint · FAF99 11.9%

Overall 1.67% 27,034/1,614,138 alleles · common exomes 20,710/1,461,820 · genomes 6,324/152,318 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	12.2%	8
Middle Eastern	2.97%	34
South Asian	2.92%	34
Remaining individualsnot grpmax-eligible	1.92%	52
Admixed American	1.31%	76
Ashkenazi Jewishnot grpmax-eligible	1.24%	81
European (non-Finnish)	1.06%	94
Finnishnot grpmax-eligible	0.238%	421
Amishnot grpmax-eligible	0.11%	912
East Asian	0.0134%	7,480

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.Val33=
Coding: c.99G>A
MANE Select: NM_024105
dbSNP: rs76707654
Type: single nucleotide variant
Location: chr22:49913667 (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-val33 (accessed [today's date]).

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