Is ALG8 p.Arg229Gln (c.686G>A) pathogenic?

ALG8 p.Arg229Gln (c.686G>A) is classified Uncertain significance in ALG8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-11). AlphaMissense: likely benign (0.0718); Very rare (popmax 0.00516%, amr); Associated with Inborn genetic diseases.

What condition is associated with ALG8 p.Arg229Gln (c.686G>A)?

ALG8 p.Arg229Gln (c.686G>A) is associated with Inborn genetic diseases (ClinVar).

How common is ALG8 p.Arg229Gln (c.686G>A) in the general population?

ALG8 p.Arg229Gln (c.686G>A) is very rare (popmax 0.00516%, amr) (gnomAD).

What do computational predictors say about ALG8 p.Arg229Gln (c.686G>A)?

AlphaMissense predicts likely benign (score 0.0718) — an in-silico prediction, not a clinical call.

ALG8 p.Arg229Gln

c.686G>A · rs756061099 · VCV3111400

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0718 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00516%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0718	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -2.42	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.20	acceptor loss · deltas
Pangolin	Δ0.22	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.09	GERP -0.79, phastCons 0.002
Regional constraint	o/e 0.94	unconstrained · MANE · 39 kb · p 0.14 · regional, not allelic
Overall
CADD	15.95	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00516% Admixed American · 3/58,148 alleles

Filtering AF 0.00137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00068%

Overall 0.000562% 9/1,601,892 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00516%	19,383
African / African-American	0.00134%	74,572
European (non-Finnish)	0.000426%	234,815

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.Arg229Gln
Coding: c.686G>A
MANE Select: NM_024079
dbSNP: rs756061099
Type: single nucleotide variant
Location: chr11:78113977 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.07
Residue 229: a UniProt-annotated variant site (in pcld3)

Full ALG8 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

Similar variants

ALG8 p.Arg229Ter Pathogenic/Likely pathogenic ★★ same residue
ALG8 p.Ala250Val Uncertain significance ★★ ⚠ same condition
ALG8 p.Ala388Pro Uncertain significance ★★ ⚠ same condition
ALG8 p.Ala403Thr Uncertain significance ★★ ⚠ same condition
ALG8 p.Ala424Val Uncertain significance ★★ ⚠ same condition
ALG8 p.Ala72Val Uncertain significance ★★ ⚠ same condition
ALG8 p.Arg215Gln Uncertain significance ★★ ⚠ same condition
ALG8 p.Gly130Glu Uncertain significance ★★ ⚠ 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-arg229gln (accessed [today's date]).

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