Is ALG12 p.Pro215= (c.645G>A) pathogenic?

ALG12 p.Pro215= (c.645G>A) is classified Benign/Likely benign in ALG12 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-02). Low-frequency (popmax 1.96%, afr); Associated with ALG12-congenital disorder of glycosylation.

What condition is associated with ALG12 p.Pro215= (c.645G>A)?

ALG12 p.Pro215= (c.645G>A) is associated with ALG12-congenital disorder of glycosylation (ClinVar).

How common is ALG12 p.Pro215= (c.645G>A) in the general population?

ALG12 p.Pro215= (c.645G>A) is low-frequency (popmax 1.96%, afr) (gnomAD).

How is ALG12-CDG inherited?

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

ALG12 p.Pro215=

c.645G>A · rs12167668 · VCV166674

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.96%, afr)

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 -20	GERP -3.1
Overall
CADD	0.029	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.96% African / African-American · 1,470/75,074 alleles

Filtering AF 1.87% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.84%

Overall 0.11% 1,769/1,614,128 alleles · low-frequency exomes 947/1,461,742 · genomes 822/152,386 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.96%	51
Admixed American	0.122%	822
Remaining individualsnot grpmax-eligible	0.0944%	1,059
Middle Eastern	0.033%	3,031
European (non-Finnish)	0.0136%	7,329
South Asian	0.00329%	30,363
East Asian	0.00223%	44,892

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.Pro215=
Coding: c.645G>A
MANE Select: NM_024105
dbSNP: rs12167668
Type: single nucleotide variant
Location: chr22:49909913 (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.Pro215Leu Uncertain significance ★★ ⚠ same residue
ALG12 p.Pro215Ala Uncertain significance ★ ⚠ 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

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-pro215 (accessed [today's date]).

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