IL6R p.Asp358Val

Variant names:

• chr1-154454494-A-T
• rs2228145
• NM_000565.4:c.1073A>T
• IL6R p.Asp358Val

Your query was ambiguous. Multiple possible variants found:

• chr1-154454494-A-T
• chr1-154454494-AT-TA
• chr1-154454494-AT-TC
• chr1-154454494-AT-TG

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateB3_Supporting

The NM_000565.4(IL6R):c.1073A>T (p.Asp358Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene IL6R is a tumor suppressor gene (CancerMine: 1 TSG, 1 oncogene citations). The gene IL6R is a known oncogene (CancerMine: 1 TSG, 1 oncogene 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 benign. Variant has been reported in ClinVar as Uncertain Significance (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.D358A: Benign/Likely_benign (ClinVar VariationId 14660, 2 stars); p.D358Y: Uncertain_significance (ClinVar VariationId 1362683, 1 star)

• Frequency: Genomes: not found (cov: 30)
• Consequence: IL6R NM_000565.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.519
• Publications: 2 publications found

Genes affected

IL6R (HGNC:6019): (interleukin 6 receptor) This gene encodes a subunit of the interleukin 6 (IL6) receptor complex. Interleukin 6 is a potent pleiotropic cytokine that regulates cell growth and differentiation and plays an important role in the immune response. The IL6 receptor is a protein complex consisting of this protein and interleukin 6 signal transducer (IL6ST/GP130/IL6-beta), a receptor subunit also shared by many other cytokines. Dysregulated production of IL6 and this receptor are implicated in the pathogenesis of many diseases, such as multiple myeloma, autoimmune diseases and prostate cancer. Alternatively spliced transcript variants encoding distinct isoforms have been identified in this gene. A pseudogene of this gene is found on chromosome 9. [provided by RefSeq, Aug 2020]

IL6R Gene-Disease associations (from GenCC):

• hyper-IgE recurrent infection syndrome 5, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 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])
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000565.4. 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
	IL6R NM_000565.4	MANE Select	c.1073A>T p.Asp358Val	missense	Exon 9 of 10	Prot: NP_000556.1 UniProt:
	IL6R NM_001382769.1		c.1172A>T p.Asp391Val	missense	Exon 10 of 11	Prot: NP_001369698.1
	IL6R NM_001382770.1		c.1166A>T p.Asp389Val	missense	Exon 10 of 11	Prot: NP_001369699.1

IL6R NM_000565.4

MANE Select

HGVSc / HGVSpc.1073A>Tp.Asp358Val

Exon rankExon 9 of 10

missense

Prot: NP_000556.1UniProt: A0N0L5P08887-1

IL6R NM_001382769.1

HGVSc / HGVSpc.1172A>Tp.Asp391Val

Exon rankExon 10 of 11

missense

Prot: NP_001369698.1

IL6R NM_001382770.1

HGVSc / HGVSpc.1166A>Tp.Asp389Val

Exon rankExon 10 of 11

missense

Prot: NP_001369699.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	IL6R ENST00000368485.8	TSL:1MANE Select	c.1073A>T p.Asp358Val	missense	Exon 9 of 10	Prot: ENSP00000357470.3 UniProt:
	IL6R ENST00000344086.8	TSL:1	c.1066+4514A>T	intron	Intron 8 of 8	Prot: ENSP00000340589.4 UniProt:
	IL6R ENST00000858510.1		c.1265A>T p.Asp422Val	missense	Exon 11 of 12	Prot: ENSP00000528569.1 UniProt:

IL6R ENST00000368485.8

TSL:1MANE Select

HGVSc / HGVSpc.1073A>Tp.Asp358Val

Exon rankExon 9 of 10

missense

Prot: ENSP00000357470.3UniProt: P08887-1

IL6R ENST00000344086.8

TSL:1

HGVSc / HGVSpc.1066+4514A>T

Exon rankIntron 8 of 8

intron

Prot: ENSP00000340589.4UniProt: P08887-2

IL6R ENST00000858510.1

HGVSc / HGVSpc.1265A>Tp.Asp422Val

Exon rankExon 11 of 12

missense

Prot: ENSP00000528569.1UniProt: A0ACI8RD36

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:30
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:30

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	18
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Benign	0.81
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.32	N
FuncVEP CTI	Benign	0.015
GPN-Star LLR	N/A	-3.7
GPN-Star score	N/A	3.7
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-0.89	T
Mutation Taster	N/A	95/5	polymorphism
PhyloP100	Benign	0.52
popEVE	Benign	-3.1
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.14
Sift	Benign	0.20	T
Sift4G	Benign	0.19	T
Varity_R	N/A	0.25
VESM-3B	Benign	-7.6

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
DS_AL_spliceai	Uncertain	0.29	Position offset: -6
Pangolin (max)	Uncertain	0.21
Pangolin gain	Benign	0.14	Position offset: 12
Pangolin loss	Uncertain	0.21	Position offset: -6
SpliceAI score (max)	Uncertain	0.29	Details are displayed if max score is > 0.2

Showing 5 of 5 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: rs2228145;

hg19: chr1-154426970;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar