Is ALG8 p.Tyr463Cys (c.1388A>G) pathogenic?

ALG8 p.Tyr463Cys (c.1388A>G) is classified Uncertain significance in ALG8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-11). AlphaMissense: likely benign (0.2873); Very rare (popmax 0.000508%, nfe); Associated with ALG8-related disorder.

What condition is associated with ALG8 p.Tyr463Cys (c.1388A>G)?

ALG8 p.Tyr463Cys (c.1388A>G) is associated with ALG8-related disorder (ClinVar).

How common is ALG8 p.Tyr463Cys (c.1388A>G) in the general population?

ALG8 p.Tyr463Cys (c.1388A>G) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about ALG8 p.Tyr463Cys (c.1388A>G)?

AlphaMissense predicts likely benign (score 0.2873) — an in-silico prediction, not a clinical call.

ALG8 p.Tyr463Cys

c.1388A>G · rs1859778993 · VCV2631013

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2873 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALG8-related disorder

Computational evidence

Protein change
AlphaMissense	0.2873	likely benign
REVEL	0.896	moderately pathogenic-leaning
SaProt	LLR -14.74	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 39 kb · p 0.14 · regional, not allelic
Overall
CADD	27.8	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 0.000508% European (non-Finnish) · 6/1,180,022 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00041% 6/1,461,866 alleles · very 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: ALG8
Protein: p.Tyr463Cys
Coding: c.1388A>G
MANE Select: NM_024079
dbSNP: rs1859778993
Type: single nucleotide variant
Location: chr11:78101157 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.07
Residue 463: a UniProt-annotated variant site (in pcld3)

Full ALG8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ALG8-related disorder

Similar variants

ALG8 c.777+1G>A Likely pathogenic ★★ same condition
ALG8 p.Arg179Ter Pathogenic/Likely pathogenic ★★ same condition
ALG8 p.Arg268Ter Pathogenic/Likely pathogenic ★★ same condition
ALG8 p.Pro425Gln Uncertain significance ★★ ⚠ same condition
ALG8 c.898+1G>T Likely pathogenic same condition
ALG8 p.Phe143Cys Uncertain significance ⚠ same condition
ALG8 p.Asp86= Likely benign same condition
ALG8 p.Ser404= Likely benign 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/alg8-p-tyr463cys (accessed [today's date]).

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