Is INVS p.Arg779Trp (c.2335C>T) pathogenic?

INVS p.Arg779Trp (c.2335C>T) is classified Uncertain significance in INVS (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-03-17). AlphaMissense: likely benign (0.0754); Ultra-rare (popmax 0.024%, afr); Associated with Inborn genetic diseases.

What condition is associated with INVS p.Arg779Trp (c.2335C>T)?

INVS p.Arg779Trp (c.2335C>T) is associated with Inborn genetic diseases, nephronophthisis 2, nephronophthisis (ClinVar).

How common is INVS p.Arg779Trp (c.2335C>T) in the general population?

INVS p.Arg779Trp (c.2335C>T) is ultra-rare (popmax 0.024%, afr) (gnomAD).

What do computational predictors say about INVS p.Arg779Trp (c.2335C>T)?

AlphaMissense predicts likely benign (score 0.0754) — an in-silico prediction, not a clinical call.

INVS p.Arg779Trp

c.2335C>T · rs370643191 · VCV364230

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0754 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.024%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0754	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -9.15	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 0.39	GERP -2.6, phastCons 0.018
Regional constraint	o/e 0.99	unconstrained · MANE · 16 kb · p 0.9 · regional, not allelic
Overall
CADD	19.95	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 0.024% African / African-American · 18/74,912 alleles

Filtering AF 0.0155% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.00446% 72/1,614,060 alleles · ultra-rare exomes 62/1,461,892 · genomes 10/152,168 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.024%	4,162
South Asian	0.00768%	13,013
Remaining individualsnot grpmax-eligible	0.0064%	15,622
European (non-Finnish)	0.00356%	28,096
Admixed American	0.00167%	59,998

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.Arg779Trp
Coding: c.2335C>T
MANE Select: NM_014425
dbSNP: rs370643191
Type: single nucleotide variant
Location: chr9:100292592 (GRCh38)
Gene constraint: LOEUF 0.941 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.76
Residue 779: 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 2 nephronophthisis

Similar variants

INVS p.Arg779Gln Uncertain significance ★★ ⚠ same residue
INVS p.Arg779= Conflicting classifications of pathogenicity ★ 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

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-arg779trp (accessed [today's date]).

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