Is INVS p.Lys596Arg (c.1787A>G) pathogenic?

INVS p.Lys596Arg (c.1787A>G) is classified Conflicting classifications of pathogenicity in INVS (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-06-03). AlphaMissense: likely benign (0.1542); Ultra-rare (popmax 0.0347%, afr); Associated with nephronophthisis.

What condition is associated with INVS p.Lys596Arg (c.1787A>G)?

INVS p.Lys596Arg (c.1787A>G) is associated with nephronophthisis, nephronophthisis 2 (ClinVar).

How common is INVS p.Lys596Arg (c.1787A>G) in the general population?

INVS p.Lys596Arg (c.1787A>G) is ultra-rare (popmax 0.0347%, afr) (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.Lys596Arg (c.1787A>G)?

AlphaMissense predicts likely benign (score 0.1542) — an in-silico prediction, not a clinical call.

INVS p.Lys596Arg

c.1787A>G · rs751587570 · VCV1385733

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1542 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0347%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.1542	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -6.33	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.67	acceptor gain · deltas
Pangolin	Δ0.45	gain · loss 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 38 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0347% African / African-American · 26/74,956 alleles

Filtering AF 0.0243% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0208%

Overall 0.00174% 28/1,613,138 alleles · ultra-rare exomes 11/1,460,868 · genomes 17/152,270 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0347%	2,883
East Asian	0.00223%	44,902
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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.Lys596Arg
Coding: c.1787A>G
MANE Select: NM_014425
dbSNP: rs751587570
Type: single nucleotide variant
Location: chr9:100284322 (GRCh38)
Gene constraint: LOEUF 0.941 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.76
Residue 596: 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

Also linked: nephronophthisis 2

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-lys596arg (accessed [today's date]).

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