Is ALG1 p.Lys322Arg (c.965A>G) pathogenic?

ALG1 p.Lys322Arg (c.965A>G) is classified Uncertain significance in ALG1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-02-18). AlphaMissense: likely benign (0.0728); Rare (popmax 0.113%, mid); Associated with ALG1-congenital disorder of glycosylation.

What condition is associated with ALG1 p.Lys322Arg (c.965A>G)?

ALG1 p.Lys322Arg (c.965A>G) is associated with ALG1-congenital disorder of glycosylation (ClinVar).

How common is ALG1 p.Lys322Arg (c.965A>G) in the general population?

ALG1 p.Lys322Arg (c.965A>G) is rare (popmax 0.113%, mid) (gnomAD).

How is ALG1-CDG inherited?

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

What do computational predictors say about ALG1 p.Lys322Arg (c.965A>G)?

AlphaMissense predicts likely benign (score 0.0728) — an in-silico prediction, not a clinical call.

ALG1 p.Lys322Arg

c.965A>G · rs145851409 · VCV1061103

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0728 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.113%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ALG1-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.0728	likely benign
REVEL	0.374	indeterminate
SaProt	LLR -10.13	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.78	acceptor gain · deltas
Pangolin	Δ0.56	gain · loss 0.05 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3	GERP -1.5, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 13 kb · p 3.2e-11 · regional, not allelic
Overall
CADD	30.0	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 0.113% Middle Eastern · 5/4,428 alleles

Filtering AF 0.0444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0288%

Overall 0.00407% 65/1,596,354 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.113%	886
African / African-American	0.0107%	9,370
Remaining individualsnot grpmax-eligible	0.00482%	20,740
European (non-Finnish)	0.00398%	25,101
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,598
South Asian	0.0011%	90,988

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.Lys322Arg
Coding: c.965A>G
MANE Select: NM_019109
dbSNP: rs145851409
Type: single nucleotide variant
Location: chr16:5080949 (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

For ALG1-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ALG1 p.Lys322Gln Uncertain significance ★ ⚠ same residue
ALG1 p.Lys322Ile Uncertain significance ★ ⚠ 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

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-lys322arg (accessed [today's date]).

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