ATP7B p.Arg952Lys

Variant names:

• chr13-51949672-C-T
• rs732774
• NM_000053.4:c.2855G>A
• ATP7B p.Arg952Lys

Your query was ambiguous. Multiple possible variants found:

• chr13-51949672-C-T
• chr13-51949671-TC-CT

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-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). O7_SupportingO8_SupportingB1_Strong

The NM_000053.4(ATP7B):c.2855G>A (p.Arg952Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene ATP7B is a known oncogene (CancerMine: 1 oncogene citations). The variant allele was found at a cumulative frequency of 0.577 (AC=930,537) in the gnomAD database across 1,613,064 control chromosomes, including 270,218 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.627. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R952S: Uncertain_significance (ClinVar VariationId 3459534, 1 star) The variant has been observed in cBioPortal in 3 samples across 3 studies and 2 cancer types; somatic enrichment level: SUPPORTING_LOW (Observed in a small number of cBioPortal cases.). 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: 𝑓 0.56 (24237 hom., cov: 33)
  • Exomes 𝑓: 0.58 (245981 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Predictors: REVEL: 0.43: Uncertain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:20
• Conservation: PhyloP100: 2.25
• Publications: 94 publications found

Genes affected

ATP7B (HGNC:870): (ATPase copper transporting beta) This gene is a member of the P-type cation transport ATPase family and encodes a protein with several membrane-spanning domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least 2 putative copper-binding sites. This protein is a monomer, and functions as a copper-transporting ATPase which exports copper out of the cells, such as the efflux of hepatic copper into the bile. Alternate transcriptional splice variants, encoding different isoforms with distinct cellular localizations, have been characterized. Mutations in this gene have been associated with Wilson disease which is characterized by copper accumulation. [provided by RefSeq, Dec 2019]

ATP7B Gene-Disease associations (from GenCC):

• Wilson disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Natera, ClinGen, Genomics England PanelApp, Orphanet

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O7Mutational hotspot or critical domain		Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 1 pathogenic, 1 benign (OR vs. background: 5.0); Variant does not impact splicing — splice-hotspot path not applicable
	O8Missense constraint in gene or region		Missense in gene/domain constrained for missense variation where missense is common disease mechanism (O8 supporting); Gene/disease mechanism: missense is a common mechanism of oncogenesis; gnomAD missense Z-score: 0.84 (threshold ≥3.09 for constraint); Domain-level constraint: variant is in a critically constrained functional domain (IS_AT_CRITICAL_DOMAIN)
	B1High frequency in general population		GnomAD effective popmax AF >1% — B1 stand-alone benign; GnomAD effective popmax AF = 0.627 — exceeds 1% threshold (B1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000053.4. 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
	ATP7B NM_000053.4	MANE Select	c.2855G>A p.Arg952Lys	missense	Exon 12 of 21	Prot: NP_000044.2
	ATP7B NM_001406511.1		c.2855G>A p.Arg952Lys	missense	Exon 13 of 22	Prot: NP_001393440.1
	ATP7B NM_001406512.1		c.2855G>A p.Arg952Lys	missense	Exon 13 of 22	Prot: NP_001393441.1

ATP7B NM_000053.4

MANE Select

HGVSc / HGVSpc.2855G>Ap.Arg952Lys

Exon rankExon 12 of 21

missense

Prot: NP_000044.2

ATP7B NM_001406511.1

HGVSc / HGVSpc.2855G>Ap.Arg952Lys

Exon rankExon 13 of 22

missense

Prot: NP_001393440.1

ATP7B NM_001406512.1

HGVSc / HGVSpc.2855G>Ap.Arg952Lys

Exon rankExon 13 of 22

missense

Prot: NP_001393441.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ATP7B ENST00000242839.10	MANE Select	c.2855G>A p.Arg952Lys	missense	Exon 12 of 21	Prot: ENSP00000242839
	ATP7B ENST00000634844.2	TSL:1	c.2711G>A p.Arg904Lys	missense	Exon 12 of 21	Prot: ENSP00000489398
	ATP7B ENST00000418097.8	TSL:1	c.2855G>A p.Arg952Lys	missense	Exon 12 of 20	Prot: ENSP00000393343

ATP7B ENST00000242839.10

MANE Select

HGVSc / HGVSpc.2855G>Ap.Arg952Lys

Exon rankExon 12 of 21

missense

Prot: ENSP00000242839

ATP7B ENST00000634844.2

TSL:1

HGVSc / HGVSpc.2711G>Ap.Arg904Lys

Exon rankExon 12 of 21

missense

Prot: ENSP00000489398

ATP7B ENST00000418097.8

TSL:1

HGVSc / HGVSpc.2855G>Ap.Arg952Lys

Exon rankExon 12 of 20

missense

Prot: ENSP00000393343

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.563	AC:85554	Hom:24228	AN:151968	Cov:33
GnomAD2 exomes	AF: 0.567	AC:141220	Hom:	AN:249058	Cov:
GnomAD4 exome	AF: 0.578	AC:844929	Hom:245981	AN:1460978	Cov:60
GnomAD4 genome	AF: 0.563	AC:85608	Hom:24237	AN:152086	Cov:33
TOPMed (Bravo)	AF: 0.563	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.575	AC:335992	Hom:96764	AN:584442	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.585	AC:1369	Hom:400	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.420	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.553	AC:166	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.572	AC:6861	Hom:	AN:12002	Cov:
GenomeAsia100K	AF: 0.527	AC:1827	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.402	AC:2911	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.705	AC:124	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.405	AC:49729	Hom:10146	AN:122752	Cov:
Turkish Variome	AF: 0.602	AC:4047	Hom:1252	AN:6720	Cov:
UK10K	AF: 0.589	AC:4453	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.415	AC:3715	Hom:766	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.563 *	6258	11106	0.569 *	10019	17610
BipEx(Bipolar disorder (including schizoaffective))	0.583	16572	28420	0.576	16625	28844
Epi25(Epilepsy)	0.570	23896	41958	0.579	38713	66884
SCHEMA(Schizophrenia)	0.544	89026	163738	0.558	154829	277260

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	9	Wilson disease (9)
-	1	1	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	16
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	15
DANN	Benign	0.77
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.32	N
GPN-Star LLR	N/A	8.5
GPN-Star score	N/A	4.1
LIST_S2	Benign	0.016	T
MetaRNN	Benign	0.00035	T
MetaSVM	Benign	-0.96	T
Mutation Taster	N/A	99/1	polymorphism (auto)
MutationAssessor	Benign	-0.41	N
PhyloP100	Benign	2.2
popEVE	Benign	-2.5
PrimateAI	Benign	0.46	T
PROVEAN	Benign	1.2	N
REVEL	Uncertain	0.43
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Varity_R	N/A	0.12
VESM-3B	Benign	-4.4

Showing 26 of 26 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.080	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

dbSNP: rs732774;

hg19: chr13-52523808;

COSMIC: COSV54436520;

COSMIC: COSV54436520;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar