X-154532268-AC-GG

Variant names:

• chrX-154532268-AC-GG
• NM_001360016.2:c.1376_1377delGTinsCC
• G6PD p.Arg459Pro

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+4 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 4 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO7_SupportingO8_Supporting

The NM_001360016.2(G6PD):c.1376_1377delGTinsCC (p.Arg459Pro) variant causes a missense change. The gene G6PD is a known oncogene (CancerMine: 1 TSG, 25 oncogene, 3 driver citations). The gene G6PD is a cancer driver gene (CancerMine: 1 TSG, 25 oncogene, 3 driver 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R459C: Likely_pathogenic (ClinVar VariationId 1469858, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.69
• Publications: 0 publications found

Genes affected

G6PD (HGNC:4057): (glucose-6-phosphate dehydrogenase) This gene encodes glucose-6-phosphate dehydrogenase. This protein is a cytosolic enzyme encoded by a housekeeping X-linked gene whose main function is to produce NADPH, a key electron donor in the defense against oxidizing agents and in reductive biosynthetic reactions. G6PD is remarkable for its genetic diversity. Many variants of G6PD, mostly produced from missense mutations, have been described with wide ranging levels of enzyme activity and associated clinical symptoms. G6PD deficiency may cause neonatal jaundice, acute hemolysis, or severe chronic non-spherocytic hemolytic anemia. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

G6PD Gene-Disease associations (from GenCC):

• anemia, nonspherocytic hemolytic, due to G6PD deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
• G6PD deficiency

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• class I glucose-6-phosphate dehydrogenase deficiency

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 4 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])
	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: 17 pathogenic, 0 benign (OR vs. background: 175.0); 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: not available (stub — GNOMAD_MISSENSE_Z_SCORE not provided); Domain-level constraint: variant is in a critically constrained functional domain (IS_AT_CRITICAL_DOMAIN)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001360016.2. 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
	G6PD NM_001360016.2	MANE Select	c.1376_1377delGTinsCC p.Arg459Pro	missense	N/A	Prot: NP_001346945.1 UniProt:
	G6PD NM_000402.4		c.1466_1467delGTinsCC p.Arg489Pro	missense	N/A	Prot: NP_000393.4 UniProt:
	G6PD NM_001042351.3		c.1376_1377delGTinsCC p.Arg459Pro	missense	N/A	Prot: NP_001035810.1 UniProt:

G6PD NM_001360016.2

MANE Select

HGVSc / HGVSpc.1376_1377delGTinsCCp.Arg459Pro

Exon rankN/A

missense

Prot: NP_001346945.1UniProt: A0A384NL00P11413-1

G6PD NM_000402.4

HGVSc / HGVSpc.1466_1467delGTinsCCp.Arg489Pro

Exon rankN/A

missense

Prot: NP_000393.4UniProt: P11413-3

G6PD NM_001042351.3

HGVSc / HGVSpc.1376_1377delGTinsCCp.Arg459Pro

Exon rankN/A

missense

Prot: NP_001035810.1UniProt: P11413-1A0A384NL00

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	G6PD ENST00000393562.10	TSL:1MANE Select	c.1376_1377delGTinsCC p.Arg459Pro	missense	N/A	Prot: ENSP00000377192.3 UniProt:
	G6PD ENST00000696421.1		c.1376_1377delGTinsCC p.Arg459Pro	missense	N/A	Prot: ENSP00000512616.1 UniProt:
	G6PD ENST00000369620.6	TSL:5	c.1514_1515delGTinsCC p.Arg505Pro	missense	N/A	Prot: ENSP00000358633.2 UniProt:

G6PD ENST00000393562.10

TSL:1MANE Select

HGVSc / HGVSpc.1376_1377delGTinsCCp.Arg459Pro

Exon rankN/A

missense

Prot: ENSP00000377192.3UniProt: P11413-1

G6PD ENST00000696421.1

HGVSc / HGVSpc.1376_1377delGTinsCCp.Arg459Pro

Exon rankN/A

missense

Prot: ENSP00000512616.1UniProt: A0A8Q3SIS5

G6PD ENST00000369620.6

TSL:5

HGVSc / HGVSpc.1514_1515delGTinsCCp.Arg505Pro

Exon rankN/A

missense

Prot: ENSP00000358633.2UniProt: P11413-2

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:23
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:23

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	3.7

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.

2 no calibration

2 assays found for this variant.

No calibration: 2 assays (score only).

None of these data are clinically calibrated — they are not validated, so interpret them with great caution.

Protein level

G6PD Yeast Growth Scores

G6PD Yeast Growth

• Gene: G6PD
• Assay type: Cell proliferation assay with genetic complementation
• Mechanism: Molecular function
• Model system: Yeast
• Score: · p.Arg459Pro (assay numbering)

No calibration data

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Protein level

G6PD VAMP-seq Scores

G6PD VAMP-seq

• Gene: G6PD
• Assay type: Flow cytometry assay
• Mechanism: Loss of function
• Model system: Immortalized human cells
• Score: 0.859 · p.Arg459Pro (assay numbering)

No calibration data

This score is at approximately the 46th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Other links and lift over

hg19: chrX-153760483;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar