Is ALG8 p.Ser146Leu (c.437C>T) pathogenic?

ALG8 p.Ser146Leu (c.437C>T) is classified Uncertain significance in ALG8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-08). AlphaMissense: likely benign (0.1693); Very rare (popmax 0.0022%, sas); Associated with Inborn genetic diseases.

What condition is associated with ALG8 p.Ser146Leu (c.437C>T)?

ALG8 p.Ser146Leu (c.437C>T) is associated with Inborn genetic diseases, ALG8-congenital disorder of glycosylation, polycystic liver disease 3 with or without kidney cysts (ClinVar).

How common is ALG8 p.Ser146Leu (c.437C>T) in the general population?

ALG8 p.Ser146Leu (c.437C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about ALG8 p.Ser146Leu (c.437C>T)?

AlphaMissense predicts likely benign (score 0.1693) — an in-silico prediction, not a clinical call.

ALG8 p.Ser146Leu

c.437C>T · VCV3574070

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1693 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1693	likely benign
REVEL	0.499	indeterminate
SaProt	LLR -11.08	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.20	donor loss, 41 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 39 kb · p 0.14 · regional, not allelic
Overall
CADD	23.8	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 0.0022% South Asian · 2/91,066 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000744% 12/1,613,756 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,533
European (non-Finnish)	0.000847%	117,999

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.Ser146Leu
Coding: c.437C>T
MANE Select: NM_024079
Type: single nucleotide variant
Location: chr11:78121106 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.07

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

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

Similar variants

ALG8 p.Ser146= Uncertain significance ★ same residue
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

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-ser146leu (accessed [today's date]).

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