Is ALG6 p.Ala333Val (c.998C>T) pathogenic?

ALG6 p.Ala333Val (c.998C>T) is classified Pathogenic in ALG6 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-01-18). AlphaMissense: likely pathogenic (0.8076); Very rare (popmax 0.00739%, nfe); Associated with ALG6-related disorder.

What condition is associated with ALG6 p.Ala333Val (c.998C>T)?

ALG6 p.Ala333Val (c.998C>T) is associated with ALG6-related disorder, ALG6-congenital disorder of glycosylation 1C (ClinVar).

How common is ALG6 p.Ala333Val (c.998C>T) in the general population?

ALG6 p.Ala333Val (c.998C>T) is very rare (popmax 0.00739%, nfe) (gnomAD).

What do computational predictors say about ALG6 p.Ala333Val (c.998C>T)?

AlphaMissense predicts likely pathogenic (score 0.8076) — an in-silico prediction, not a clinical call.

ALG6 p.Ala333Val

c.998C>T · rs121908443 · VCV5497

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

AlphaMissense

likely pathogenic

0.8076 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00739%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALG6-related disorder

Computational evidence

Protein change
AlphaMissense	0.8076	likely pathogenic ✓ concordant with ClinVar
REVEL	0.863	moderately pathogenic-leaning
SaProt	LLR -11.34	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 66 kb · p 0.00074 · regional, not allelic
Overall
CADD	28.8	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 0.00739% European (non-Finnish) · 87/1,177,232 alleles

Filtering AF 0.00606% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00566%

Overall 0.00609% 98/1,608,452 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00739%	13,531
Remaining individualsnot grpmax-eligible	0.00482%	20,766
South Asian	0.00444%	22,527
Finnishnot grpmax-eligible	0.00315%	31,709
Admixed American	0.00168%	59,672
African / African-American	0.00134%	74,716

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: ALG6
Protein: p.Ala333Val
Coding: c.998C>T
MANE Select: NM_013339
dbSNP: rs121908443
Type: single nucleotide variant
Location: chr1:63419380 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.08
Residue 333: a UniProt-annotated variant site (in cdg1c)

Full ALG6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ALG6-related disorder

Also linked: ALG6-congenital disorder of glycosylation 1C

Similar variants

ALG6 p.Ala333= Likely benign ★★ same residue
ALG6 p.Ala333Pro Uncertain significance ★ ⚠ same residue
ALG6 p.Ala333Gly Uncertain significance ★ ⚠ same residue
ALG6 c.1128-1G>A Likely pathogenic ★★ same condition
ALG6 c.1128-2A>C Likely pathogenic ★★ same condition
ALG6 c.1326+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALG6 c.257+5G>A Pathogenic/Likely pathogenic ★★ same condition
ALG6 c.429+1G>T 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/alg6-p-ala333val (accessed [today's date]).

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