Is ALG13 p.Ser228= (c.684C>T) pathogenic?

ALG13 p.Ser228= (c.684C>T) is classified Likely benign in ALG13 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-14). Very rare (popmax 0.00067%, nfe); Associated with developmental and epileptic encephalopathy, 36.

What condition is associated with ALG13 p.Ser228= (c.684C>T)?

ALG13 p.Ser228= (c.684C>T) is associated with developmental and epileptic encephalopathy, 36 (ClinVar).

How common is ALG13 p.Ser228= (c.684C>T) in the general population?

ALG13 p.Ser228= (c.684C>T) is very rare (popmax 0.00067%, nfe) (gnomAD).

How is ALG13-CDG inherited?

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

ALG13 p.Ser228=

c.684C>T · rs2525565864 · VCV2803903

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00067%, nfe)

Conditions

developmental and epileptic encephalopathy, 36

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.16	GERP 0.85, phastCons 0.97
Overall
CADD	9.098	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00067% European (non-Finnish) · 6/895,365 alleles

Filtering AF 0.000241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000158%

Overall 0.000495% 6/1,211,712 alleles · very rare exomes 6/1,097,943 · genomes 0/113,769 · joint denominator

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.Ser228=
Coding: c.684C>T
MANE Select: NM_001099922
dbSNP: rs2525565864
Type: single nucleotide variant
Location: chrX:111708327 (GRCh38)
Structure: AlphaFold pLDDT 54.42
Residue 228: 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.Ser228Ile Uncertain significance ★ ⚠ same residue
ALG13 p.Ser228Asn Likely benign ★ ⚠ 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

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-ser228 (accessed [today's date]).

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