Is ALG12 p.Pro291Leu (c.872C>T) pathogenic?

ALG12 p.Pro291Leu (c.872C>T) is classified Conflicting classifications of pathogenicity in ALG12 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-12-14). AlphaMissense: likely benign (0.0524); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with ALG12 p.Pro291Leu (c.872C>T)?

ALG12 p.Pro291Leu (c.872C>T) is associated with Inborn genetic diseases, ALG12-congenital disorder of glycosylation (ClinVar).

How common is ALG12 p.Pro291Leu (c.872C>T) in the general population?

ALG12 p.Pro291Leu (c.872C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about ALG12 p.Pro291Leu (c.872C>T)?

AlphaMissense predicts likely benign (score 0.0524) — an in-silico prediction, not a clinical call.

ALG12 p.Pro291Leu

c.872C>T · rs778608834 · VCV1438937

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0524 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0524	likely benign
REVEL	0.272	benign-leaning
SaProt	LLR -4.29	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9	GERP 0.69, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 9,924 bp · p 0.17 · regional, not allelic
Overall
CADD	14.09	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.00161% 26/1,613,858 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.015%	6,666
South Asian	0.0022%	45,541
African / African-American	0.00134%	74,892
European (non-Finnish)	0.0011%	90,770

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.Pro291Leu
Coding: c.872C>T
MANE Select: NM_024105
dbSNP: rs778608834
Type: single nucleotide variant
Location: chr22:49907841 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ALG12-congenital disorder of glycosylation

Similar variants

ALG12 p.Pro291Ser Uncertain significance ★ ⚠ same residue
ALG12 p.Pro291= Likely benign ★ 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-pro291leu (accessed [today's date]).

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