Is CORIN p.Ser4fs (c.8dup) pathogenic?

CORIN p.Ser4fs (c.8dup) is classified Conflicting classifications of pathogenicity in CORIN (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2019-12-05). Low-frequency (popmax 1.28%, eas); Associated with preeclampsia/eclampsia 5.

What condition is associated with CORIN p.Ser4fs (c.8dup)?

CORIN p.Ser4fs (c.8dup) is associated with preeclampsia/eclampsia 5 (ClinVar).

How common is CORIN p.Ser4fs (c.8dup) in the general population?

CORIN p.Ser4fs (c.8dup) is low-frequency (popmax 1.28%, eas) (gnomAD).

How is Preeclampsia inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

CORIN p.Ser4fs

c.8dup · rs199972616 · VCV225326

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

low-frequency (popmax 1.28%, eas)

Conditions

preeclampsia/eclampsia 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 22
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.65	GERP 0.98
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.28% East Asian · 575/44,884 alleles

Filtering AF 1.19% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.16%

Overall 0.039% 629/1,613,208 alleles · low-frequency exomes 569/1,460,880 · genomes 60/152,328 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	1.28%	78
Remaining individualsnot grpmax-eligible	0.0352%	2,841
Admixed American	0.035%	2,858
South Asian	0.00329%	30,361
European (non-Finnish)	0.000678%	147,504

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CORIN
Protein: p.Ser4fs
Coding: c.8dup
MANE Select: NM_006587
dbSNP: rs199972616
Type: Duplication
Location: chr4:47837941 (GRCh38)
Gene constraint: LOEUF 1.042 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.20
Residue 4: the 'disordered' region

Full CORIN gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

preeclampsia/eclampsia 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Preeclampsia (Orphanet):

Inheritance: Not applicable
Onset: Adult
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

CORIN p.Ser683Cys Benign/Likely benign ★★ ⚠ same condition
CORIN p.Tyr576Cys Uncertain significance ★ ⚠ same condition
CORIN p.Lys317Glu Pathogenic ⚠ same condition
CORIN p.Ser472Gly Pathogenic ⚠ same condition
LRP4 p.Leu1836fs Uncertain significance ★★ same type
LRP4 c.2093-15dup Benign ★★ same type
CORIN p.Met229fs Pathogenic ★ same type
LRP4 p.Asn1467fs Pathogenic ★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/corin-p-ser4fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown