Is INVS p.Arg613Trp (c.1837C>T) pathogenic?

INVS p.Arg613Trp (c.1837C>T) is classified Uncertain significance in INVS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-24). AlphaMissense: likely benign (0.0642); Very rare (popmax 0.000593%, nfe); Associated with Inborn genetic diseases.

What condition is associated with INVS p.Arg613Trp (c.1837C>T)?

INVS p.Arg613Trp (c.1837C>T) is associated with Inborn genetic diseases, nephronophthisis (ClinVar).

How common is INVS p.Arg613Trp (c.1837C>T) in the general population?

INVS p.Arg613Trp (c.1837C>T) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about INVS p.Arg613Trp (c.1837C>T)?

AlphaMissense predicts likely benign (score 0.0642) — an in-silico prediction, not a clinical call.

INVS p.Arg613Trp

c.1837C>T · rs529208660 · VCV940220

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0642 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0642	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -9.24	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.15	GERP -1.3
Regional constraint	o/e 0.74	unconstrained · MANE · 38 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	18.09	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 0.000593% European (non-Finnish) · 7/1,180,038 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,613,672 alleles · very rare exomes 7/1,461,348 · genomes 0/152,324 · joint denominator

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.Arg613Trp
Coding: c.1837C>T
MANE Select: NM_014425
dbSNP: rs529208660
Type: single nucleotide variant
Location: chr9:100284372 (GRCh38)
Gene constraint: LOEUF 0.941 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.76
Residue 613: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis

Similar variants

INVS p.Arg613= Likely benign ★ same residue
INVS p.Arg613Gln Uncertain significance ★ ⚠ same residue
INVS p.Arg613Pro 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

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-arg613trp (accessed [today's date]).

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