12-111803962-GAA-AAG

Variant names:

• chr12-111803962-GAA-AAG
• NM_000690.4:c.1510_1512delGAAinsAAG
• ALDH2 p.Glu504Lys

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Moderate

The NM_000690.4(ALDH2):c.1510_1512delGAAinsAAG (p.Glu504Lys) variant causes a missense change. The gene ALDH2 is a tumor suppressor gene (CancerMine: 1 TSG, 1 oncogene citations). The gene ALDH2 is a known oncogene (CancerMine: 1 TSG, 1 oncogene citations). Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.78). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.E504K: drug_response (ClinVar VariationId 18390, 3 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ALDH2 NM_000690.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.78
• Publications: 0 publications found

Genes affected

ALDH2 (HGNC:404): (aldehyde dehydrogenase 2 family member) This protein belongs to the aldehyde dehydrogenase family of proteins. Aldehyde dehydrogenase is the second enzyme of the major oxidative pathway of alcohol metabolism. Two major liver isoforms of aldehyde dehydrogenase, cytosolic and mitochondrial, can be distinguished by their electrophoretic mobilities, kinetic properties, and subcellular localizations. Most Caucasians have two major isozymes, while approximately 50% of East Asians have the cytosolic isozyme but not the mitochondrial isozyme. A remarkably higher frequency of acute alcohol intoxication among East Asians than among Caucasians could be related to the absence of a catalytically active form of the mitochondrial isozyme. The increased exposure to acetaldehyde in individuals with the catalytically inactive form may also confer greater susceptibility to many types of cancer. This gene encodes a mitochondrial isoform, which has a low Km for acetaldehydes, and is localized in mitochondrial matrix. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Nov 2016]

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000690.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ALDH2 NM_000690.4	MANE Select	c.1510_1512delGAAinsAAG p.Glu504Lys	missense	N/A	Prot: NP_000681.2
	ALDH2 NM_001204889.2		c.1369_1371delGAAinsAAG p.Glu457Lys	missense	N/A	Prot: NP_001191818.1 UniProt:

ALDH2 NM_000690.4

MANE Select

HGVSc / HGVSpc.1510_1512delGAAinsAAGp.Glu504Lys

Exon rankN/A

missense

Prot: NP_000681.2

ALDH2 NM_001204889.2

HGVSc / HGVSpc.1369_1371delGAAinsAAGp.Glu457Lys

Exon rankN/A

missense

Prot: NP_001191818.1UniProt: P05091-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ALDH2 ENST00000261733.7	TSL:1MANE Select	c.1510_1512delGAAinsAAG p.Glu504Lys	missense	N/A	Prot: ENSP00000261733.2 UniProt:
	ALDH2 ENST00000871406.1		c.1621_1623delGAAinsAAG p.Glu541Lys	missense	N/A	Prot: ENSP00000541465.1 UniProt:
	ALDH2 ENST00000871417.1		c.1618_1620delGAAinsAAG p.Glu540Lys	missense	N/A	Prot: ENSP00000541476.1 UniProt:

ALDH2 ENST00000261733.7

TSL:1MANE Select

HGVSc / HGVSpc.1510_1512delGAAinsAAGp.Glu504Lys

Exon rankN/A

missense

Prot: ENSP00000261733.2UniProt: P05091-1

ALDH2 ENST00000871406.1

HGVSc / HGVSpc.1621_1623delGAAinsAAGp.Glu541Lys

Exon rankN/A

missense

Prot: ENSP00000541465.1UniProt: A0ACI8RCU5

ALDH2 ENST00000871417.1

HGVSc / HGVSpc.1618_1620delGAAinsAAGp.Glu540Lys

Exon rankN/A

missense

Prot: ENSP00000541476.1UniProt: A0ACI8QM20

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	9.8

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr12-112241766;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar