20-35176751-A-G

Variant names:

• chr20-35176751-A-G
• rs867186
• NM_006404.5:c.655A>G
• PROCR p.Ser219Gly

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-5 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -5 classification points (ACGS-UK Somatic Oncogenicity v2025). B1_StrongB3_Supporting

The NM_006404.5(PROCR):c.655A>G (p.Ser219Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene PROCR is a tumor suppressor gene (CancerMine: 1 TSG citations). The variant allele was found at a cumulative frequency of 0.0968 (AC=156,250) in the gnomAD database across 1,613,772 control chromosomes, including 8,351 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.174. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The variant has been observed in cBioPortal in 2 samples across 2 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.

• Frequency:
  • Genomes: 𝑓 0.097 (803 hom., cov: 32)
  • Exomes 𝑓: 0.097 (7548 hom.)
• Consequence: PROCR NM_006404.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.105
• Publications: 67 publications found

Genes affected

PROCR (HGNC:9452): (protein C receptor) The protein encoded by this gene is a receptor for activated protein C, a serine protease activated by and involved in the blood coagulation pathway. The encoded protein is an N-glycosylated type I membrane protein that enhances the activation of protein C. Mutations in this gene have been associated with venous thromboembolism and myocardial infarction, as well as with late fetal loss during pregnancy. The encoded protein may also play a role in malarial infection and has been associated with cancer. [provided by RefSeq, Jul 2013]

MMP24-AS1-EDEM2 (HGNC:):

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	B1High frequency in general population		GnomAD effective popmax AF >1% — B1 stand-alone benign; GnomAD effective popmax AF = 0.174 — exceeds 1% threshold (B1 applied)
	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_006404.5. 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
	PROCR NM_006404.5	MANE Select	c.655A>G p.Ser219Gly	missense	Exon 4 of 4	Prot: NP_006395.2
	MMP24-AS1-EDEM2 NM_001355008.2		c.-101-10880T>C	intron	Intron 4 of 14	Prot: NP_001341937.1

PROCR NM_006404.5

MANE Select

HGVSc / HGVSpc.655A>Gp.Ser219Gly

Exon rankExon 4 of 4

missense

Prot: NP_006395.2

MMP24-AS1-EDEM2 NM_001355008.2

HGVSc / HGVSpc.-101-10880T>C

Exon rankIntron 4 of 14

intron

Prot: NP_001341937.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PROCR ENST00000216968.5	TSL:1MANE Select	c.655A>G p.Ser219Gly	missense	Exon 4 of 4	Prot: ENSP00000216968.3 UniProt:
	PROCR ENST00000852804.1		c.655A>G p.Ser219Gly	missense	Exon 5 of 5	Prot: ENSP00000522863.1 UniProt:
	PROCR ENST00000852805.1		c.655A>G p.Ser219Gly	missense	Exon 5 of 5	Prot: ENSP00000522864.1 UniProt:

PROCR ENST00000216968.5

TSL:1MANE Select

HGVSc / HGVSpc.655A>Gp.Ser219Gly

Exon rankExon 4 of 4

missense

Prot: ENSP00000216968.3UniProt: Q9UNN8

PROCR ENST00000852804.1

HGVSc / HGVSpc.655A>Gp.Ser219Gly

Exon rankExon 5 of 5

missense

Prot: ENSP00000522863.1UniProt: Q9UNN8

PROCR ENST00000852805.1

HGVSc / HGVSpc.655A>Gp.Ser219Gly

Exon rankExon 5 of 5

missense

Prot: ENSP00000522864.1UniProt: Q9UNN8

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: 0.0968	AC:14725	Hom:788	AN:152054	Cov:32
GnomAD2 exomes	AF: 0.103	AC:25922	Hom:	AN:250950	Cov:
GnomAD4 exome	AF: 0.0968	AC:141482	Hom:7548	AN:1461600	Cov:36
GnomAD4 genome	AF: 0.0970	AC:14768	Hom:803	AN:152172	Cov:32
TOPMed (Bravo)	AF: 0.0892	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0975	AC:73068	Hom:3725	AN:749032	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0760	AC:178	Hom:5	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0710	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.0967	AC:29	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0992	AC:1290	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.137	AC:475	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.0370	AC:269	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.0993	AC:199	Hom:	AN:2004	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0389	AC:4756	Hom:81	AN:122304	Cov:
Turkish Variome	AF: 0.135	AC:909	Hom:66	AN:6716	Cov:
UK10K	AF: 0.0895	AC:677	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.0817	AC:732	Hom:37	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.117 *	1297	11092	0.117 *	2048	17534
BipEx(Bipolar disorder (including schizoaffective))	0.0993	2822	28420	0.104	2988	28844
Epi25(Epilepsy)	0.100	4210	41956	0.0917	6131	66876
SCHEMA(Schizophrenia)	0.116	14418	123840	0.117	22673	193950

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

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	14
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.36	N
FuncVEP CTI	Benign	0.015
GPN-Star LLR	N/A	-5.0
GPN-Star score	N/A	5.0
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.95	T
Mutation Taster	N/A	98/2	polymorphism (auto)
MutationAssessor	Benign	1.6	L
PhyloP100	Benign	0.10
popEVE	Benign	-3.2
PrimateAI	Benign	0.33	T
PromoterAI	N/A	-0.022	Neutral
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.057
Sift	Benign	0.031	D
Sift4G	Uncertain	0.050	T
Varity_R	N/A	0.043
VESM-3B	Benign	-6.7

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.030	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: rs867186;

hg19: chr20-33764554;

COSMIC: COSV53826500;

COSMIC: COSV53826500;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar