NM_001360016.2:c.1376G>C

Variant names:

• chrX-154532269-C-G
• rs72554665
• NM_001360016.2:c.1376G>C
• G6PD p.Arg459Pro

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 14 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM5PP3_ModeratePP5_Strong

The NM_001360016.2(G6PD):c.1376G>C (p.Arg459Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000661 (AC=8) in the gnomAD database across 1,209,746 control chromosomes, including 4 hemizygotes. The grpmax filtering allele frequency (95% CI) is 0.000279. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000914284: Functional assays demonstrate that the p.Arg459Pro variant results in reduced enzyme activity, between 2% and 9.5% of normal (Calabro et al. 1993" and additional evidence is available in 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: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 4 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 3.69
• Publications: 6 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000914284: Functional assays demonstrate that the p.Arg459Pro variant results in reduced enzyme activity, between 2% and 9.5% of normal (Calabro et al. 1993; Barisic et al. 2005).; SCV002599394: Decreased activity in red blood cells (1-14%) (PS3).
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 17 pathogenic, 0 benign (OR vs. background: 175.0).
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R459C: Likely_pathogenic (ClinVar VariationId 1469858, 1 star)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

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.1376G>C p.Arg459Pro	missense	Exon 12 of 13	Prot: NP_001346945.1 UniProt:
	G6PD NM_000402.4		c.1466G>C p.Arg489Pro	missense	Exon 12 of 13	Prot: NP_000393.4 UniProt:
	G6PD NM_001042351.3		c.1376G>C p.Arg459Pro	missense	Exon 12 of 13	Prot: NP_001035810.1 UniProt:

G6PD NM_001360016.2

MANE Select

HGVSc / HGVSpc.1376G>Cp.Arg459Pro

Exon rankExon 12 of 13

missense

Prot: NP_001346945.1UniProt: A0A384NL00P11413-1

G6PD NM_000402.4

HGVSc / HGVSpc.1466G>Cp.Arg489Pro

Exon rankExon 12 of 13

missense

Prot: NP_000393.4UniProt: P11413-3

G6PD NM_001042351.3

HGVSc / HGVSpc.1376G>Cp.Arg459Pro

Exon rankExon 12 of 13

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.1376G>C p.Arg459Pro	missense	Exon 12 of 13	Prot: ENSP00000377192.3 UniProt:
	G6PD ENST00000696421.1		c.1376G>C p.Arg459Pro	missense	Exon 12 of 13	Prot: ENSP00000512616.1 UniProt:
	G6PD ENST00000369620.6	TSL:5	c.1514G>C p.Arg505Pro	missense	Exon 12 of 13	Prot: ENSP00000358633.2 UniProt:

G6PD ENST00000393562.10

TSL:1MANE Select

HGVSc / HGVSpc.1376G>Cp.Arg459Pro

Exon rankExon 12 of 13

missense

Prot: ENSP00000377192.3UniProt: P11413-1

G6PD ENST00000696421.1

HGVSc / HGVSpc.1376G>Cp.Arg459Pro

Exon rankExon 12 of 13

missense

Prot: ENSP00000512616.1UniProt: A0A8Q3SIS5

G6PD ENST00000369620.6

TSL:5

HGVSc / HGVSpc.1514G>Cp.Arg505Pro

Exon rankExon 12 of 13

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000179	AC:2	Hom:0	AN:112037	Cov:23
GnomAD2 exomes	AF: 0.0000110	AC:2	Hom:	AN:181938	Cov:
GnomAD4 exome	AF: 0.00000547	AC:6	Hom:0	AN:1097709	Cov:37
GnomAD4 genome	AF: 0.0000179	AC:2	Hom:0	AN:112037	Cov:23
TOPMed (Bravo)	AF: 0.00000378	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000159	AC:1	Hom:0	AN:62928	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
Turkish Variome	AF: 0.000189	AC:1	Hom:0	AN:4830	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000238	1	41958	0.00	0	66886

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Anemia, nonspherocytic hemolytic, due to G6PD deficiency (4)
1	-	-	G6PD deficiency (1)
1	-	-	Malaria, susceptibility to (1)
1	-	-	not provided (1)
-	-	-	G6PD COSENZA (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D
FATHMM_MKL	Uncertain	0.92	D
FuncVEP CTI	Pathogenic	1.0
GPN-Star LLR	N/A	-7.4
GPN-Star score	N/A	7.4
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.99	D
Mutation Taster	N/A	0/100	disease causing (ClinVar)
MutationAssessor	Uncertain	2.7	M
PhyloP100	Benign	3.7
popEVE	Benign	-4.2
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.84
Sift	Benign	0.080	T
Sift4G	Benign	0.097	T
Varity_R	N/A	0.98
VESM-3B	Benign	-12

Showing 26 of 26 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.070
SpliceAI score (max)	Benign	0.14	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.

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

dbSNP: rs72554665;

hg19: chrX-153760484;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar