Is ALG6 p.Pro467Leu (c.1400C>T) pathogenic?

ALG6 p.Pro467Leu (c.1400C>T) is classified Uncertain significance in ALG6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-23). AlphaMissense: ambiguous (0.4112); Ultra-rare (popmax 0.0165%, mid); Associated with ALG6-congenital disorder of glycosylation 1C.

What condition is associated with ALG6 p.Pro467Leu (c.1400C>T)?

ALG6 p.Pro467Leu (c.1400C>T) is associated with ALG6-congenital disorder of glycosylation 1C (ClinVar).

How common is ALG6 p.Pro467Leu (c.1400C>T) in the general population?

ALG6 p.Pro467Leu (c.1400C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is ALG6-CDG inherited?

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

What do computational predictors say about ALG6 p.Pro467Leu (c.1400C>T)?

AlphaMissense predicts ambiguous (score 0.4112) — an in-silico prediction, not a clinical call.

ALG6 p.Pro467Leu

c.1400C>T · rs548994709 · VCV598653

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4112 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

ALG6-congenital disorder of glycosylation 1C

Computational evidence

Protein change
AlphaMissense	0.4112	ambiguous
REVEL	0.777	moderately pathogenic-leaning
SaProt	LLR -12.37	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 66 kb · p 0.00074 · regional, not allelic
Overall
CADD	27.9	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000991% 16/1,613,856 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Admixed American	0.0117%	8,573
South Asian	0.0022%	45,536
Remaining individualsnot grpmax-eligible	0.0016%	62,498
European (non-Finnish)	0.000424%	235,963

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.Pro467Leu
Coding: c.1400C>T
MANE Select: NM_013339
dbSNP: rs548994709
Type: single nucleotide variant
Location: chr1:63436896 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.08

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

Disease context

ALG6-congenital disorder of glycosylation 1C — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For ALG6-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ALG6 p.Pro467Ser Uncertain significance ★ ⚠ same residue
ALG6 p.Pro467= Likely benign ★ same residue
ALG6 p.Pro467fs 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-pro467leu (accessed [today's date]).

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