Is ALG1 p.Ala418fs (c.1250_1251insTG) pathogenic?

ALG1 p.Ala418fs (c.12501251insTG) is classified Pathogenic/Likely pathogenic in ALG1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-04-16). Very rare (popmax 0.00333%, amr); Associated with ALG1-congenital disorder of glycosylation.

What condition is associated with ALG1 p.Ala418fs (c.1250_1251insTG)?

ALG1 p.Ala418fs (c.1250_1251insTG) is associated with ALG1-congenital disorder of glycosylation, congenital disorder of glycosylation (ClinVar).

How common is ALG1 p.Ala418fs (c.1250_1251insTG) in the general population?

ALG1 p.Ala418fs (c.1250_1251insTG) is very rare (popmax 0.00333%, amr) (gnomAD).

How is ALG1-CDG inherited?

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

ALG1 p.Ala418fs

c.1250_1251insTG · rs746019074 · VCV424339

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

ALG1-congenital disorder of glycosylation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (12 of 13, 13 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.7	GERP 1.4, phastCons 0.99
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	seg dup	· reads may not map uniquely · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,990 alleles

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

Overall 0.000688% 11/1,597,720 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0169%	5,921
Admixed Americangrpmax	0.00333%	29,995
European (non-Finnish)	0.000339%	294,943

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ALG1
Protein: p.Ala418fs
Coding: c.1250_1251insTG
MANE Select: NM_019109
dbSNP: rs746019074
Type: Insertion
Location: chr16:5083744 (GRCh38)
Gene constraint: LOEUF 1.419 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.24

Full ALG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ALG1-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital disorder of glycosylation

For ALG1-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ALG1 p.Ala418Ser Uncertain significance ★ ⚠ same residue
ALG1 c.208+19_208+20insTATG Uncertain significance ★★ same condition
ALG1 p.Gly134fs Pathogenic ★ same condition
ALG1 c.208+17_208+18insCGTC Likely benign ★ same condition
ALG1 c.208+18_208+19insATCT Likely benign ★ same condition
ALG1 c.208+19_208+20insTTTG Likely benign ★ same condition
ALG1 c.1187+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALG1 c.1187+2T>C Pathogenic ★★ 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/alg1-p-ala418fs (accessed [today's date]).

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