Is ALG13 p.Pro294Ala (c.880C>G) pathogenic?

ALG13 p.Pro294Ala (c.880C>G) is classified Conflicting classifications of pathogenicity in ALG13 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-03-27). AlphaMissense: likely pathogenic (0.5735); Ultra-rare (popmax 0.0221%, amr); Associated with developmental and epileptic encephalopathy, 36.

What condition is associated with ALG13 p.Pro294Ala (c.880C>G)?

ALG13 p.Pro294Ala (c.880C>G) is associated with developmental and epileptic encephalopathy, 36 (ClinVar).

How common is ALG13 p.Pro294Ala (c.880C>G) in the general population?

ALG13 p.Pro294Ala (c.880C>G) is ultra-rare (popmax 0.0221%, amr) (gnomAD).

How is ALG13-CDG inherited?

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

What do computational predictors say about ALG13 p.Pro294Ala (c.880C>G)?

AlphaMissense predicts likely pathogenic (score 0.5735) — an in-silico prediction, not a clinical call.

ALG13 p.Pro294Ala

c.880C>G · rs753556936 · VCV589561

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5735 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0221%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 36

Computational evidence

Protein change
AlphaMissense	0.5735	likely pathogenic
REVEL	0.22	benign-leaning
SaProt	LLR -7.85	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 5.3, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 8,848 bp · p 0.46 · regional, not allelic
Overall
CADD	24.6	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 0.0221% Admixed American · 10/45,323 alleles

Filtering AF 0.0119% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00908%

Overall 0.000914% 11/1,202,944 alleles · ultra-rare exomes 9/1,091,078 · genomes 2/111,866 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0221%	4,532
East Asian	0.00298%	33,589

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: ALG13
Protein: p.Pro294Ala
Coding: c.880C>G
MANE Select: NM_001099922
dbSNP: rs753556936
Type: single nucleotide variant
Location: chrX:111711720 (GRCh38)
Structure: AlphaFold pLDDT 54.42
Residue 294: the otu domain; the 'deubiquitinase activity' region

Full ALG13 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental and epileptic encephalopathy, 36 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For ALG13-CDG (Orphanet):

Inheritance: X-linked recessive
Onset: Infancy, Neonatal

Similar variants

ALG13 p.Pro294Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
ALG13 p.Asn107Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
ALG13 c.2458-1G>A Uncertain significance ★★ same condition
ALG13 c.2695+4G>A Uncertain significance ★★ same condition
ALG13 c.2932+6T>C Uncertain significance ★★ same condition
ALG13 c.834+3A>G Uncertain significance ★★ same condition
ALG13 c.932+2T>C Uncertain significance ★★ same condition
ALG13 p.Ala1044Thr 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/alg13-p-pro294ala (accessed [today's date]).

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