Is ALG3 p.Leu20His (c.59T>A) pathogenic?

ALG3 p.Leu20His (c.59T>A) is classified Uncertain significance in ALG3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-24). AlphaMissense: likely benign (0.0825); Very rare (popmax 0.00484%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ALG3 p.Leu20His (c.59T>A)?

ALG3 p.Leu20His (c.59T>A) is associated with Inborn genetic diseases (ClinVar).

How common is ALG3 p.Leu20His (c.59T>A) in the general population?

ALG3 p.Leu20His (c.59T>A) is very rare (popmax 0.00484%, nfe) (gnomAD).

What do computational predictors say about ALG3 p.Leu20His (c.59T>A)?

AlphaMissense predicts likely benign (score 0.0825) — an in-silico prediction, not a clinical call.

ALG3 p.Leu20His

c.59T>A · rs759012191 · VCV2529678

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0825 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00484%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0825	likely benign
REVEL	0.255	benign-leaning
SaProt	LLR -6.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -2, phastCons 0.005
Regional constraint	o/e 1.09	unconstrained · MANE · 3,742 bp · p 0.14 · regional, not allelic
Overall
CADD	12.29	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 0.00484% European (non-Finnish) · 57/1,176,532 alleles

Filtering AF 0.00379% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00346%

Overall 0.00374% 60/1,605,546 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00484%	20,641
Remaining individualsnot grpmax-eligible	0.00322%	31,035
East Asian	0.00224%	44,624

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: ALG3
Protein: p.Leu20His
Coding: c.59T>A
MANE Select: NM_005787
dbSNP: rs759012191
Type: single nucleotide variant
Location: chr3:184248882 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.05

Full ALG3 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

ALG3 p.Leu20Phe Uncertain significance ★ ⚠ same residue
ALG3 p.Ala102Ser Uncertain significance ★★ ⚠ same condition
ALG3 p.Arg229Cys Uncertain significance ★★ ⚠ same condition
ALG3 p.Arg27Gly Uncertain significance ★★ ⚠ same condition
ALG3 p.Arg378Cys Uncertain significance ★★ ⚠ same condition
ALG3 p.Asn83Ser Uncertain significance ★★ ⚠ same condition
ALG3 p.Cys21Gly Uncertain significance ★★ ⚠ same condition
ALG3 p.Cys21Phe 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/alg3-p-leu20his (accessed [today's date]).

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