Is ALG11 p.Leu46Pro (c.137T>C) pathogenic?

ALG11 p.Leu46Pro (c.137T>C) is classified Uncertain significance in ALG11 (ClinVar, Single submitter, 2 submitters; last evaluated 2015-02-07). AlphaMissense: ambiguous (0.4321); Very rare (popmax 0.00223%, eas); Associated with ALG11-congenital disorder of glycosylation.

What condition is associated with ALG11 p.Leu46Pro (c.137T>C)?

ALG11 p.Leu46Pro (c.137T>C) is associated with ALG11-congenital disorder of glycosylation (ClinVar).

How common is ALG11 p.Leu46Pro (c.137T>C) in the general population?

ALG11 p.Leu46Pro (c.137T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

How is ALG11-CDG inherited?

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

What do computational predictors say about ALG11 p.Leu46Pro (c.137T>C)?

AlphaMissense predicts ambiguous (score 0.4321) — an in-silico prediction, not a clinical call.

ALG11 p.Leu46Pro

c.137T>C · rs794727256 · VCV195102

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4321 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

ALG11-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.4321	ambiguous
REVEL	0.677	pathogenic-leaning
SaProt	LLR -14.17	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 16 kb · p 0.068 · regional, not allelic
Overall
CADD	26.0	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 0.00223% East Asian · 1/44,846 alleles

Overall 6.84e-05% 1/1,461,802 alleles · very rare

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: ALG11
Protein: p.Leu46Pro
Coding: c.137T>C
MANE Select: NM_001004127
dbSNP: rs794727256
Type: single nucleotide variant
Location: chr13:52019005 (GRCh38)
Gene constraint: LOEUF 0.908 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.40

Full ALG11 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ALG11-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For ALG11-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ALG11 c.45-2A>T Likely pathogenic ★★ same condition
ALG11 p.Arg468Cys Likely pathogenic ★★ ⚠ same condition
ALG11 p.Arg468His Likely pathogenic ★★ same condition
ALG11 p.Met1Val Likely pathogenic ★★ same condition
ALG11 c.*540T>A Uncertain significance ★★ ⚠ same condition
ALG11 p.Arg136Cys Uncertain significance ★★ same condition
ALG11 p.Arg15Thr Uncertain significance ★★ ⚠ same condition
ALG11 p.Arg346His 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/alg11-p-leu46pro (accessed [today's date]).

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