Is ALG1 p.Ala278Thr (c.832G>A) pathogenic?

ALG1 p.Ala278Thr (c.832G>A) is classified Uncertain significance in ALG1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-10). AlphaMissense: ambiguous (0.3816); Ultra-rare (popmax 0.0178%, eas); Associated with Inborn genetic diseases.

What condition is associated with ALG1 p.Ala278Thr (c.832G>A)?

ALG1 p.Ala278Thr (c.832G>A) is associated with Inborn genetic diseases, ALG1-congenital disorder of glycosylation (ClinVar).

How common is ALG1 p.Ala278Thr (c.832G>A) in the general population?

ALG1 p.Ala278Thr (c.832G>A) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about ALG1 p.Ala278Thr (c.832G>A)?

AlphaMissense predicts ambiguous (score 0.3816) — an in-silico prediction, not a clinical call.

ALG1 p.Ala278Thr

c.832G>A · rs1364564952 · VCV1365848

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3816 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3816	ambiguous
REVEL	0.638	indeterminate
SaProt	LLR -13.69	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 13 kb · p 3.2e-11 · regional, not allelic
Overall
CADD	28.7	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 0.0178% East Asian · 8/44,858 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.000496% 8/1,611,888 alleles · ultra-rare

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.Ala278Thr
Coding: c.832G>A
MANE Select: NM_019109
dbSNP: rs1364564952
Type: single nucleotide variant
Location: chr16:5078848 (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

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

Also linked: ALG1-congenital disorder of glycosylation

Similar variants

ALG1 p.Ala278= Likely benign ★ same residue
ALG1 c.1187+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALG1 c.1187+2T>C Pathogenic ★★ same condition
ALG1 c.1188-2A>G Pathogenic/Likely pathogenic ★★ same condition
ALG1 c.209-2A>G Likely pathogenic ★★ same condition
ALG1 c.539+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALG1 c.630-2A>G Likely pathogenic ★★ same condition
ALG1 c.863-2A>G 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/alg1-p-ala278thr (accessed [today's date]).

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