MECP2 p.Arg318Leu

Variant names:

• chrX-154030911-C-A
• rs61751443
• NM_001110792.2:c.953G>T
• MECP2 p.Arg318Leu

Your query was ambiguous. Multiple possible variants found:

• chrX-154030911-C-A
• chrX-154030910-GC-AA
• chrX-154030910-GC-CA
• chrX-154030910-GC-TA
• chrX-154030910-GCG-CAA
• chrX-154030910-GCG-TAA

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+7 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 7 classification points (ACGS-UK Somatic Oncogenicity v2025). O1_ModerateO3_ModerateO5_SupportingO6_SupportingO7_Supporting

The NM_001110792.2(MECP2):c.953G>T (p.Arg318Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene MECP2 is a tumor suppressor gene (CancerMine: 1 TSG, 15 oncogene, 2 driver citations). The gene MECP2 is a known oncogene (CancerMine: 1 TSG, 15 oncogene, 2 driver citations). The gene MECP2 is a cancer driver gene (CancerMine: 1 TSG, 15 oncogene, 2 driver citations). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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 (★★). A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R318H: Pathogenic/Likely_pathogenic (ClinVar VariationId 143746, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R318= (synonymous): Likely_benign (ClinVar VariationId 1127365, 1 star)

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 5.36
• Publications: 26 publications found

Genes affected

MECP2 (HGNC:6990): (methyl-CpG binding protein 2) DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 is dispensible in stem cells, but is essential for embryonic development. MECP2 gene mutations are the cause of most cases of Rett syndrome, a progressive neurologic developmental disorder and one of the most common causes of cognitive disability in females. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]

MECP2 Gene-Disease associations (from GenCC):

• Rett syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics, PanelApp Australia
• severe neonatal-onset encephalopathy with microcephaly

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• syndromic X-linked intellectual disability Lubs type

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability-psychosis-macroorchidism syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for MECP2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 7 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O1Established oncogenic variant		TSG gene: ClinVar germline P/LP ★★+ — Moderate (O1); O1 contributing sources (2.0 pts): ClinVar germline P/LP in TSG (★★)
	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])
	O5Same location/impact as known oncogenic		Different AA at same residue with oncogenic evidence (or germline P/LP in TSG), or same AA change SCI Tier II Potential — Supporting (O5); ClinVar same-AA oncogenic/T1: false | ClinVar same-AA SCI tier: — | CGI same-AA oncogenic: false | TSG: true | ClinVar same-AA germline P/LP: false | CIViC LOF: false | ClinVar diff-AA oncogenic: false | ClinVar diff-AA germline P/LP: true
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect
	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: 25 pathogenic, 2 benign (OR vs. background: 51.0); Variant does not impact splicing — splice-hotspot path not applicable

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001110792.2. 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
	MECP2 NM_001110792.2	MANE Select	c.953G>T p.Arg318Leu	missense	Exon 3 of 3	Prot: NP_001104262.1 UniProt:
	MECP2 NM_004992.4	MANE Plus Clinical	c.917G>T p.Arg306Leu	missense	Exon 4 of 4	Prot: NP_004983.1 UniProt:
	MECP2 NM_001316337.2		c.638G>T p.Arg213Leu	missense	Exon 5 of 5	Prot: NP_001303266.1

MECP2 NM_001110792.2

MANE Select

HGVSc / HGVSpc.953G>Tp.Arg318Leu

Exon rankExon 3 of 3

missense

Prot: NP_001104262.1UniProt: A0A140VKC4P51608-2

MECP2 NM_004992.4

MANE Plus Clinical

HGVSc / HGVSpc.917G>Tp.Arg306Leu

Exon rankExon 4 of 4

missense

Prot: NP_004983.1UniProt: D3YJ43P51608-1

MECP2 NM_001316337.2

HGVSc / HGVSpc.638G>Tp.Arg213Leu

Exon rankExon 5 of 5

missense

Prot: NP_001303266.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MECP2 ENST00000453960.7	TSL:1MANE Select	c.953G>T p.Arg318Leu	missense	Exon 3 of 3	Prot: ENSP00000395535.2 UniProt:
	MECP2 ENST00000303391.11	TSL:1MANE Plus Clinical	c.917G>T p.Arg306Leu	missense	Exon 4 of 4	Prot: ENSP00000301948.6 UniProt:
	MECP2 ENST00000630151.3	TSL:5	c.917G>T p.Arg306Leu	missense	Exon 4 of 4	Prot: ENSP00000486089.2 UniProt:

MECP2 ENST00000453960.7

TSL:1MANE Select

HGVSc / HGVSpc.953G>Tp.Arg318Leu

Exon rankExon 3 of 3

missense

Prot: ENSP00000395535.2UniProt: P51608-2

MECP2 ENST00000303391.11

TSL:1MANE Plus Clinical

HGVSc / HGVSpc.917G>Tp.Arg306Leu

Exon rankExon 4 of 4

missense

Prot: ENSP00000301948.6UniProt: P51608-1

MECP2 ENST00000630151.3

TSL:5

HGVSc / HGVSpc.917G>Tp.Arg306Leu

Exon rankExon 4 of 4

missense

Prot: ENSP00000486089.2UniProt: A0A0D9SEX1P51608-1

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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:23
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:35
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:23
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:23460	Cov:

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Rett syndrome (2)
-	-	-	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	29
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
FATHMM_MKL	Uncertain	0.95	D
FuncVEP CTI	Pathogenic	0.83
GPN-Star LLR	N/A	-10
GPN-Star score	N/A	10
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.79	D
Mutation Taster	N/A	12/88	disease causing
MutationAssessor	Uncertain	2.2	M
PhyloP100	Uncertain	5.4
popEVE	Benign	-3.3
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.1	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.20	T
Varity_R	N/A	0.72
VESM-3B	Benign	-11

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	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: rs61751443;

hg19: chrX-153296362;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar