Is ALG13 p.Phe252Leu (c.756T>G) pathogenic?

ALG13 p.Phe252Leu (c.756T>G) is classified Conflicting classifications of pathogenicity in ALG13 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-12-22). AlphaMissense: likely pathogenic (0.9733); Ultra-rare (popmax 0.021%, amr); Associated with developmental and epileptic encephalopathy, 36.

What condition is associated with ALG13 p.Phe252Leu (c.756T>G)?

ALG13 p.Phe252Leu (c.756T>G) is associated with developmental and epileptic encephalopathy, 36 (ClinVar).

How common is ALG13 p.Phe252Leu (c.756T>G) in the general population?

ALG13 p.Phe252Leu (c.756T>G) is ultra-rare (popmax 0.021%, 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.Phe252Leu (c.756T>G)?

AlphaMissense predicts likely pathogenic (score 0.9733) — an in-silico prediction, not a clinical call.

ALG13 p.Phe252Leu

c.756T>G · rs915629293 · VCV574279

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9733 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.021%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 36

Computational evidence

Protein change
AlphaMissense	0.9733	likely pathogenic · top 4% in ALG13
REVEL	0.203	benign-leaning
SaProt	LLR -8.49	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 1.8	GERP 4.9, phastCons 1
Regional constraint	o/e 0.28	constrained · MANE · 698 bp · p 5.1e-05 · regional, not allelic
Overall
CADD	23.0	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 0.021% Admixed American · 9/42,919 alleles

Filtering AF 0.0109% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0081%

Overall 0.00127% 15/1,176,936 alleles · ultra-rare exomes 8/1,065,039 · genomes 7/111,897 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.021%	4,769
Remaining individualsnot grpmax-eligible	0.013%	7,680

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.Phe252Leu
Coding: c.756T>G
MANE Select: NM_001099922
dbSNP: rs915629293
Type: single nucleotide variant
Location: chrX:111708970 (GRCh38)
Structure: AlphaFold pLDDT 54.42
Residue 252: 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.Phe252= 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
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-phe252leu (accessed [today's date]).

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