Is ALG12 p.Pro238= (c.714G>A) pathogenic?

ALG12 p.Pro238= (c.714G>A) is classified Conflicting classifications of pathogenicity in ALG12 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-01). Very rare (popmax 0.00833%, amr); Associated with ALG12-congenital disorder of glycosylation.

What condition is associated with ALG12 p.Pro238= (c.714G>A)?

ALG12 p.Pro238= (c.714G>A) is associated with ALG12-congenital disorder of glycosylation (ClinVar).

How common is ALG12 p.Pro238= (c.714G>A) in the general population?

ALG12 p.Pro238= (c.714G>A) is very rare (popmax 0.00833%, amr) (gnomAD).

How is ALG12-CDG inherited?

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

ALG12 p.Pro238=

c.714G>A · rs760973218 · VCV901173

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

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 -15	GERP -2.9
Overall
CADD	0.419	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00833% Admixed American · 5/60,008 alleles

Filtering AF 0.00375% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00337%

Overall 0.00483% 78/1,614,098 alleles · very rare exomes 66/1,461,888 · genomes 12/152,210 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0109%	9,148
Admixed Americangrpmax	0.00833%	12,002
African / African-American	0.00667%	14,988
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	0.00475%	21,072
East Asian	0.00223%	44,894
South Asian	0.0011%	91,086

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro238=
Coding: c.714G>A
MANE Select: NM_024105
dbSNP: rs760973218
Type: single nucleotide variant
Location: chr22:49909298 (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.Pro238Leu 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
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-pro238 (accessed [today's date]).

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