Is ALG12 p.Leu433His (c.1298T>A) pathogenic?

ALG12 p.Leu433His (c.1298T>A) is classified Uncertain significance in ALG12 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-06). AlphaMissense: likely pathogenic (0.9489); Absent from gnomAD v4.1.

How common is ALG12 p.Leu433His (c.1298T>A) in the general population?

ALG12 p.Leu433His (c.1298T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ALG12 p.Leu433His (c.1298T>A)?

AlphaMissense predicts likely pathogenic (score 0.9489) — an in-silico prediction, not a clinical call.

ALG12 p.Leu433His

c.1298T>A · rs2060528902 · VCV1809890

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9489 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9489	likely pathogenic · top 3% in ALG12
REVEL	0.76	pathogenic-leaning
SaProt	LLR -16.05	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 9,924 bp · p 0.17 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ALG12
Protein: p.Leu433His
Coding: c.1298T>A
MANE Select: NM_024105
dbSNP: rs2060528902
Type: single nucleotide variant
Location: chr22:49904007 (GRCh38)
Gene constraint: LOEUF 0.965 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.26
Residue 433: a UniProt-annotated variant site (in cdg1g)

Full ALG12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ALG12 p.Leu433= Conflicting classifications of pathogenicity ★ same residue
ALG12 p.Leu433fs Likely pathogenic ★ same residue
ALG12 c.295+1G>A Pathogenic/Likely pathogenic ★★ same type
ALG12 c.768+1G>A Likely pathogenic ★★ same type
ALG12 p.Arg146Gln Pathogenic/Likely pathogenic ★★ same type
ALG12 p.Arg202Ter Pathogenic/Likely pathogenic ★★ same type
ALG12 p.Gly101Arg Likely pathogenic ★★ same type
ALG12 p.Thr67Met Pathogenic/Likely pathogenic ★★ same type

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/alg12-p-leu433his (accessed [today's date]).

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