12-111803962-G-A

Variant names:

• chr12-111803962-G-A
• rs671
• NM_000690.4:c.1510G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000690.4(ALDH2):​c.1510G>A​(p.Glu504Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00704 in 1,608,410 control chromosomes in the GnomAD database, including 1,380 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (141 hom., cov: 31)
  • Exomes 𝑓: 0.0070 (1239 hom.)
• Consequence: ALDH2 NM_000690.4 missense
• Clinical Significance: drug response reviewed by expert panel P:2 U:1 B:1 O:5
• Conservation: PhyloP100: 9.78
• Publications: 1193 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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001886636).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Variant Effect in Transcripts

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

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH2	NM_000690.4	MANE Select	c.1510G>A	p.Glu504Lys	missense	Exon 12 of 13	NP_000681.2
	ALDH2	NM_001204889.2		c.1369G>A	p.Glu457Lys	missense	Exon 11 of 12	NP_001191818.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH2	ENST00000261733.7	TSL:1 MANE Select	c.1510G>A	p.Glu504Lys	missense	Exon 12 of 13	ENSP00000261733.2
	ALDH2	ENST00000416293.7	TSL:2	c.1369G>A	p.Glu457Lys	missense	Exon 11 of 12	ENSP00000403349.3
	ALDH2	ENST00000548536.1	TSL:3	n.*1386G>A		non_coding_transcript_exon	Exon 13 of 14	ENSP00000448179.1

Frequencies

GnomAD3 genomes AF: 0.00787 AC: 1196 AN: 152056 Hom.: 141 Cov.: 31

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000918

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.0189 AC: 4582 AN: 242666 AF XY: 0.0176

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000390

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.254

Gnomad FIN exome AF: 0.0000471

Gnomad NFE exome AF: 0.0000274

Gnomad OTH exome AF: 0.00555

GnomAD4 exome AF: 0.00695 AC: 10123 AN: 1456236 Hom.: 1239 Cov.: 30 AF XY: 0.00689 AC XY: 4989 AN XY: 724228

African (AFR) AF: 0.000150 AC: 5 AN: 33356

American (AMR) AF: 0.000318 AC: 14 AN: 44064

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25992

East Asian (EAS) AF: 0.246 AC: 9690 AN: 39376

South Asian (SAS) AF: 0.000222 AC: 19 AN: 85490

European-Finnish (FIN) AF: 0.0000377 AC: 2 AN: 53036

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.0000361 AC: 40 AN: 1109086

Other (OTH) AF: 0.00586 AC: 352 AN: 60078

GnomAD4 genome AF: 0.00784 AC: 1193 AN: 152174 Hom.: 141 Cov.: 31 AF XY: 0.00900 AC XY: 669 AN XY: 74372

African (AFR) AF: 0.000193 AC: 8 AN: 41546

American (AMR) AF: 0.000917 AC: 14 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.225 AC: 1154 AN: 5132

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.00474 AC: 10 AN: 2108

Alfa AF: 0.00590 Hom.: 432

Bravo AF: 0.00896

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ExAC AF: 0.0165 AC: 2006

Asia WGS AF: 0.0290 AC: 102 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Pathogenic:2 Uncertain:1 Benign:1 Other:5

Revision: reviewed by expert panel

Submissions by phenotype

AMED syndrome, digenic Pathogenic:2

Feb 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Mar 21, 2025

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed in the gnomAD v4.1.0 dataset (total allele frequency: 0.704%). Predicted Consequence/Location: Missense variant. Missense changes are a common disease-causing mechanism.Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 33355142). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.60 (>=0.6, sensitivity 0.68 and specificity 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000018390 / PMID: VCV000018390 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

ALDH2-related disorder Uncertain:1

Sep 21, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Alcohol dependence Benign:1

Feb 01, 2010

OMIM

Significance: protective

Review Status: no assertion criteria provided

Collection Method: literature only

ESOPHAGEAL CANCER, ALCOHOL-RELATED, SUSCEPTIBILITY TO Other:1

Feb 01, 2010

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

SUBLINGUAL NITROGLYCERIN, SUSCEPTIBILITY TO POOR RESPONSE TO Other:1

Feb 01, 2010

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Susceptibility to hangover Other:1

Feb 01, 2010

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Alcohol sensitivity, acute Other:1

Feb 12, 2021

OMIM

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: literature only

ethanol response - Toxicity Other:1

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

PharmGKB Level of Evidence 2B: Variants in Level 2B clinical annotations are not in PharmGKB’s Tier 1 VIPs. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2B clinical annotations must be supported by at least two independent publications. Drug-variant association: Toxicity

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		9.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.018	D
Polyphen		0.96	D
Vest4		0.48
MPC		1.0
ClinPred		0.10	T
GERP RS		6.0
Varity_R		0.95
gMVP		0.89
Mutation Taster		=70/30	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs671; hg19: chr12-112241766; COSMIC: COSV55665271; COSMIC: COSV55665271;