Is ALG8 p.Leu145= (c.435G>A) pathogenic?

ALG8 p.Leu145= (c.435G>A) is classified Likely benign in ALG8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-12). Ultra-rare (popmax 0.012%, afr); Associated with ALG8-congenital disorder of glycosylation.

What condition is associated with ALG8 p.Leu145= (c.435G>A)?

ALG8 p.Leu145= (c.435G>A) is associated with ALG8-congenital disorder of glycosylation (ClinVar).

How common is ALG8 p.Leu145= (c.435G>A) in the general population?

ALG8 p.Leu145= (c.435G>A) is ultra-rare (popmax 0.012%, afr) (gnomAD).

How is ALG8-CDG inherited?

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

ALG8 p.Leu145=

c.435G>A · rs113030322 · VCV2148414

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Conditions

ALG8-congenital disorder of glycosylation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.054	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.5	GERP -4.6
Overall
CADD	0.82	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.012% African / African-American · 9/75,050 alleles

Filtering AF 0.00622% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.00118% 19/1,613,968 alleles · ultra-rare exomes 19/1,461,670 · genomes 0/152,298 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.016%	6,250
African / African-Americangrpmax	0.012%	8,339

Remaining individuals 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: ALG8
Protein: p.Leu145=
Coding: c.435G>A
MANE Select: NM_024079
dbSNP: rs113030322
Type: single nucleotide variant
Location: chr11:78121108 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.07

Full ALG8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ALG8-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For ALG8-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Infancy, Neonatal

Similar variants

ALG8 c.368+2T>G Likely pathogenic ★★ same condition
ALG8 c.674-2A>G Likely pathogenic ★★ same condition
ALG8 c.777+1G>A Likely pathogenic ★★ same condition
ALG8 c.95+1G>A Likely pathogenic ★★ same condition
ALG8 p.Arg179Ter Pathogenic/Likely pathogenic ★★ same condition
ALG8 p.Arg229Ter Pathogenic/Likely pathogenic ★★ same condition
ALG8 p.Arg268Ter Pathogenic/Likely pathogenic ★★ same condition
ALG8 p.Arg364Ter Pathogenic/Likely 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/alg8-p-leu145 (accessed [today's date]).

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