Is INVS p.Pro784Ser (c.2350C>T) pathogenic?

INVS p.Pro784Ser (c.2350C>T) is classified Uncertain significance in INVS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-27). AlphaMissense: likely benign (0.0826); Very rare (popmax 8.47e-05%, nfe); Associated with nephronophthisis.

What condition is associated with INVS p.Pro784Ser (c.2350C>T)?

INVS p.Pro784Ser (c.2350C>T) is associated with nephronophthisis (ClinVar).

How common is INVS p.Pro784Ser (c.2350C>T) in the general population?

INVS p.Pro784Ser (c.2350C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Nephronophthisis inherited?

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

What do computational predictors say about INVS p.Pro784Ser (c.2350C>T)?

AlphaMissense predicts likely benign (score 0.0826) — an in-silico prediction, not a clinical call.

INVS p.Pro784Ser

c.2350C>T · rs772382992 · VCV1464174

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0826 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.0826	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -5.99	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.22	GERP -0.23, phastCons 0.001
Regional constraint	o/e 0.99	unconstrained · MANE · 16 kb · p 0.9 · regional, not allelic
Overall
CADD	7.702	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,016 alleles

Overall 0.000124% 2/1,614,150 alleles · very rare exomes 2/1,461,878 · genomes 0/152,272 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
European (non-Finnish)grpmax	8.47e-05%	1,180,016

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro784Ser
Coding: c.2350C>T
MANE Select: NM_014425
dbSNP: rs772382992
Type: single nucleotide variant
Location: chr9:100292607 (GRCh38)
Gene constraint: LOEUF 0.941 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.76
Residue 784: the 'disordered' region

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 p.Pro784Leu Uncertain significance ★★ ⚠ same residue
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

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-pro784ser (accessed [today's date]).

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