Is ALG2 p.Asp73His (c.217G>C) pathogenic?

ALG2 p.Asp73His (c.217G>C) is classified Uncertain significance in ALG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-06). AlphaMissense: ambiguous (0.4687); Ultra-rare (popmax 0.0529%, sas); Associated with congenital myasthenic syndrome 14.

What condition is associated with ALG2 p.Asp73His (c.217G>C)?

ALG2 p.Asp73His (c.217G>C) is associated with congenital myasthenic syndrome 14, ALG2-congenital disorder of glycosylation (ClinVar).

How common is ALG2 p.Asp73His (c.217G>C) in the general population?

ALG2 p.Asp73His (c.217G>C) is ultra-rare (popmax 0.0529%, sas) (gnomAD).

How is ALG2-CDG inherited?

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

What do computational predictors say about ALG2 p.Asp73His (c.217G>C)?

AlphaMissense predicts ambiguous (score 0.4687) — an in-silico prediction, not a clinical call.

ALG2 p.Asp73His

c.217G>C · rs375634924 · VCV1519701

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4687 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0529%, sas)

Conditions

congenital myasthenic syndrome 14

Computational evidence

Protein change
AlphaMissense	0.4687	ambiguous
REVEL	0.621	indeterminate
SaProt	LLR -7.86	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 3,957 bp · p 0.038 · regional, not allelic
Overall
CADD	29.3	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 0.0529% South Asian · 46/86,930 alleles

Filtering AF 0.0407% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0364%

Overall 0.00313% 49/1,564,202 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0529%	1,890
Remaining individualsnot grpmax-eligible	0.00493%	20,293

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: ALG2
Protein: p.Asp73His
Coding: c.217G>C
MANE Select: NM_033087
dbSNP: rs375634924
Type: single nucleotide variant
Location: chr9:99221678 (GRCh38)
Gene constraint: LOEUF 1.408 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.03

Full ALG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital myasthenic syndrome 14 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ALG2-congenital disorder of glycosylation

For ALG2-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ALG2 p.Asp73Glu Uncertain significance ★ ⚠ same residue
ALG2 p.Asp73Tyr Uncertain significance ★ ⚠ same residue
ALG2 p.Asp73fs Likely pathogenic ★ same residue
ALG2 p.Ala29Pro Uncertain significance ★★ ⚠ same condition
ALG2 p.Ala36Val Uncertain significance ★★ ⚠ same condition
ALG2 p.Ala71Gly Uncertain significance ★★ ⚠ same condition
ALG2 p.Ala71Val Uncertain significance ★★ ⚠ same condition
ALG2 p.Arg129Gln 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/alg2-p-asp73his (accessed [today's date]).

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