Is ALG13 p.Cys765Arg (c.2293T>C) pathogenic?

ALG13 p.Cys765Arg (c.2293T>C) is classified Uncertain significance in ALG13 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-31). AlphaMissense: likely benign (0.1349); Ultra-rare (popmax 0.0231%, mid); Associated with developmental and epileptic encephalopathy, 36.

What condition is associated with ALG13 p.Cys765Arg (c.2293T>C)?

ALG13 p.Cys765Arg (c.2293T>C) is associated with developmental and epileptic encephalopathy, 36 (ClinVar).

How common is ALG13 p.Cys765Arg (c.2293T>C) in the general population?

ALG13 p.Cys765Arg (c.2293T>C) is ultra-rare (popmax 0.0231%, mid) (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.Cys765Arg (c.2293T>C)?

AlphaMissense predicts likely benign (score 0.1349) — an in-silico prediction, not a clinical call.

ALG13 p.Cys765Arg

c.2293T>C · rs927961674 · VCV1053080

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1349 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0231%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 36

Computational evidence

Protein change
AlphaMissense	0.1349	likely benign
REVEL	0.146	moderately benign-leaning
SaProt	LLR -4.75	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 1.3	GERP 1.4, phastCons 0.98
Regional constraint	o/e 0.94	unconstrained · MANE · 23 kb · p 0.27 · regional, not allelic
Overall
CADD	16.77	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0231% Middle Eastern · 1/4,334 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.00033% 4/1,211,540 alleles · ultra-rare exomes 4/1,097,637 · genomes 0/113,903 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0231%	4,334
Remaining individualsnot grpmax-eligible	0.0021%	47,632
European (non-Finnish)	0.000223%	447,598

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.Cys765Arg
Coding: c.2293T>C
MANE Select: NM_001099922
dbSNP: rs927961674
Type: single nucleotide variant
Location: chrX:111728230 (GRCh38)
Structure: AlphaFold pLDDT 54.42

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.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
ALG13 p.Ala173Val 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-cys765arg (accessed [today's date]).

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