Is INVS p.Ser888= (c.2664T>C) pathogenic?

INVS p.Ser888= (c.2664T>C) is classified Conflicting classifications of pathogenicity in INVS (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-30). Ultra-rare (popmax 0.0681%, afr); Associated with nephronophthisis.

What condition is associated with INVS p.Ser888= (c.2664T>C)?

INVS p.Ser888= (c.2664T>C) is associated with nephronophthisis (ClinVar).

How common is INVS p.Ser888= (c.2664T>C) in the general population?

INVS p.Ser888= (c.2664T>C) is ultra-rare (popmax 0.0681%, afr) (gnomAD).

How is Nephronophthisis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

INVS p.Ser888=

c.2664T>C · rs1052867 · VCV595723

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0681%, afr)

Conditions

nephronophthisis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.3
Overall
CADD	7.794	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0681% African / African-American · 51/74,854 alleles

Filtering AF 0.0532% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0479%

Overall 0.00328% 53/1,613,618 alleles · ultra-rare exomes 21/1,461,608 · genomes 32/152,010 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0681%	1,468
Remaining individualsnot grpmax-eligible	0.0032%	31,236

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: INVS
Protein: p.Ser888=
Coding: c.2664T>C
MANE Select: NM_014425
dbSNP: rs1052867
Type: single nucleotide variant
Location: chr9:100292921 (GRCh38)
Gene constraint: LOEUF 0.941 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.76
Residue 888: a UniProt-annotated variant site (in)

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

Disease context

nephronophthisis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

INVS c.107-1G>A Likely pathogenic ★★ same condition
INVS c.1078+1G>A Pathogenic ★★ same condition
INVS c.1464+1G>T Pathogenic/Likely pathogenic ★★ same condition
INVS c.2068+2T>C Likely pathogenic ★★ same condition
INVS c.2069-1G>T Likely pathogenic ★★ same condition
INVS c.2786+1G>A Pathogenic/Likely pathogenic ★★ same condition
INVS c.2786+2T>C Pathogenic/Likely pathogenic ★★ same condition
INVS c.615+1G>A Likely pathogenic ★★ same condition

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/invs-p-ser888 (accessed [today's date]).

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