Is ALG8 p.Pro425Gln (c.1274C>A) pathogenic?

ALG8 p.Pro425Gln (c.1274C>A) is classified Uncertain significance in ALG8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-01). AlphaMissense: likely benign (0.0869); Very rare (popmax 0.00541%, amr); Associated with ALG8-related disorder.

What condition is associated with ALG8 p.Pro425Gln (c.1274C>A)?

ALG8 p.Pro425Gln (c.1274C>A) is associated with ALG8-related disorder, ALG8-congenital disorder of glycosylation, polycystic liver disease 3 with or without kidney cysts (ClinVar).

How common is ALG8 p.Pro425Gln (c.1274C>A) in the general population?

ALG8 p.Pro425Gln (c.1274C>A) is very rare (popmax 0.00541%, amr) (gnomAD).

What do computational predictors say about ALG8 p.Pro425Gln (c.1274C>A)?

AlphaMissense predicts likely benign (score 0.0869) — an in-silico prediction, not a clinical call.

ALG8 p.Pro425Gln

c.1274C>A · rs1056737656 · VCV2181408

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0869 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00541%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALG8-related disorder

Computational evidence

Protein change
AlphaMissense	0.0869	likely benign
REVEL	0.26	benign-leaning
SaProt	LLR -6.26	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.9	GERP 2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 39 kb · p 0.14 · regional, not allelic
Overall
CADD	22.6	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 0.00541% Admixed American · 3/55,470 alleles

Filtering AF 0.00144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000698%

Overall 0.000315% 5/1,586,642 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00541%	18,490
Remaining individualsnot grpmax-eligible	0.00162%	61,546
African / African-American	0.00134%	74,408

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.Pro425Gln
Coding: c.1274C>A
MANE Select: NM_024079
dbSNP: rs1056737656
Type: single nucleotide variant
Location: chr11:78104358 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.07
Residue 425: 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

Also linked: ALG8-congenital disorder of glycosylation polycystic liver disease 3 with or without kidney cysts

Similar variants

ALG8 c.368+2T>G Likely pathogenic ★★ same condition
ALG8 c.674-2A>G Likely pathogenic ★★ same condition
ALG8 c.777+1G>A Likely pathogenic ★★ same condition
ALG8 c.95+1G>A Likely pathogenic ★★ same condition
ALG8 p.Arg179Ter Pathogenic/Likely pathogenic ★★ same condition
ALG8 p.Arg229Ter Pathogenic/Likely pathogenic ★★ same condition
ALG8 p.Arg268Ter Pathogenic/Likely pathogenic ★★ same condition
ALG8 p.Arg364Ter Pathogenic/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/alg8-p-pro425gln (accessed [today's date]).

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