Is ALG1 p.Arg331Cys (c.991C>T) pathogenic?

ALG1 p.Arg331Cys (c.991C>T) is classified Conflicting classifications of pathogenicity in ALG1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.0774); Rare (popmax 0.177%, afr); Associated with Inborn genetic diseases.

What condition is associated with ALG1 p.Arg331Cys (c.991C>T)?

ALG1 p.Arg331Cys (c.991C>T) is associated with Inborn genetic diseases, ALG1-congenital disorder of glycosylation (ClinVar).

How common is ALG1 p.Arg331Cys (c.991C>T) in the general population?

ALG1 p.Arg331Cys (c.991C>T) is rare (popmax 0.177%, afr) (gnomAD).

What do computational predictors say about ALG1 p.Arg331Cys (c.991C>T)?

AlphaMissense predicts likely benign (score 0.0774) — an in-silico prediction, not a clinical call.

ALG1 p.Arg331Cys

c.991C>T · rs148933850 · VCV1326389

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0774 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.177%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0774	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -9.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.027	GERP -1.3
Regional constraint	o/e 1.27	unconstrained · MANE · 13 kb · p 3.2e-11 · regional, not allelic
Overall
CADD	17.29	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 0.177% African / African-American · 133/74,958 alleles

Filtering AF 0.153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.144%

Overall 0.00977% 156/1,596,380 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.177%	564
Remaining individualsnot grpmax-eligible	0.00804%	12,444
Admixed American	0.005%	20,003
South Asian	0.0033%	30,332
Finnishnot grpmax-eligible	0.00206%	48,658
European (non-Finnish)	0.000932%	107,248

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.Arg331Cys
Coding: c.991C>T
MANE Select: NM_019109
dbSNP: rs148933850
Type: single nucleotide variant
Location: chr16:5080975 (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.Arg331= Conflicting classifications of pathogenicity ★ 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-arg331cys (accessed [today's date]).

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