Is INVS p.Lys642Arg (c.1925A>G) pathogenic?

INVS p.Lys642Arg (c.1925A>G) is classified Conflicting classifications of pathogenicity in INVS (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0659); Rare (popmax 0.258%, afr); Associated with nephronophthisis.

What condition is associated with INVS p.Lys642Arg (c.1925A>G)?

INVS p.Lys642Arg (c.1925A>G) is associated with nephronophthisis (ClinVar).

How common is INVS p.Lys642Arg (c.1925A>G) in the general population?

INVS p.Lys642Arg (c.1925A>G) is rare (popmax 0.258%, 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.Lys642Arg (c.1925A>G)?

AlphaMissense predicts likely benign (score 0.0659) — an in-silico prediction, not a clinical call.

INVS p.Lys642Arg

c.1925A>G · rs116314059 · VCV194250

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0659 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.258%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.0659	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -5.42	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 1.8	GERP -0.005, phastCons 0.29
Regional constraint	o/e 0.99	unconstrained · MANE · 16 kb · p 0.9 · regional, not allelic
Overall
CADD	6.495	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 0.258% African / African-American · 194/75,072 alleles

Filtering AF 0.229% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.217%

Overall 0.0136% 219/1,614,176 alleles · rare exomes 113/1,461,818 · genomes 106/152,358 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.258%	387
Middle Eastern	0.0495%	2,019
Remaining individualsnot grpmax-eligible	0.0256%	3,906
Admixed American	0.00833%	12,006
South Asian	0.0011%	91,074

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.Lys642Arg
Coding: c.1925A>G
MANE Select: NM_014425
dbSNP: rs116314059
Type: single nucleotide variant
Location: chr9:100284460 (GRCh38)
Gene constraint: LOEUF 0.941 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.76
Residue 642: 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.Lys642= Likely benign ★ 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-lys642arg (accessed [today's date]).

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