Is ALG2 p.Gln406His (c.1218G>C) pathogenic?

ALG2 p.Gln406His (c.1218G>C) is classified Uncertain significance in ALG2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-09-13). AlphaMissense: likely benign (0.2616); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with ALG2 p.Gln406His (c.1218G>C)?

ALG2 p.Gln406His (c.1218G>C) is associated with Inborn genetic diseases, ALG2-congenital disorder of glycosylation, congenital myasthenic syndrome 14 (ClinVar).

How common is ALG2 p.Gln406His (c.1218G>C) in the general population?

ALG2 p.Gln406His (c.1218G>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about ALG2 p.Gln406His (c.1218G>C)?

AlphaMissense predicts likely benign (score 0.2616) — an in-silico prediction, not a clinical call.

ALG2 p.Gln406His

c.1218G>C · rs763754023 · VCV1039238

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2616 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2616	likely benign
REVEL	0.405	indeterminate
SaProt	LLR -7.67	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.43	GERP -0.067, phastCons 0.99
Regional constraint	o/e 1.09	unconstrained · MANE · 3,957 bp · p 0.038 · regional, not allelic
Overall
CADD	19.08	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 0.00333% Admixed American · 2/60,006 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.00062% 10/1,614,098 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,003
Remaining individualsnot grpmax-eligible	0.0032%	31,245
South Asian	0.0022%	45,546
European (non-Finnish)	0.000339%	295,011

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.Gln406His
Coding: c.1218G>C
MANE Select: NM_033087
dbSNP: rs763754023
Type: single nucleotide variant
Location: chr9:99217967 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ALG2-congenital disorder of glycosylation congenital myasthenic syndrome 14

Similar variants

ALG2 p.Gln406= Likely benign ★ 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
ALG2 p.Arg130Gln Uncertain significance ★★ ⚠ same condition
ALG2 p.Arg251His 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-gln406his (accessed [today's date]).

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