Is INVS p.Val35Ile (c.103G>A) pathogenic?

INVS p.Val35Ile (c.103G>A) is classified Uncertain significance in INVS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-03-12). AlphaMissense: likely benign (0.0629); Ultra-rare (popmax 0.0594%, sas); Associated with nephronophthisis 2.

What condition is associated with INVS p.Val35Ile (c.103G>A)?

INVS p.Val35Ile (c.103G>A) is associated with nephronophthisis 2, nephronophthisis (ClinVar).

How common is INVS p.Val35Ile (c.103G>A) in the general population?

INVS p.Val35Ile (c.103G>A) is ultra-rare (popmax 0.0594%, sas) (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.Val35Ile (c.103G>A)?

AlphaMissense predicts likely benign (score 0.0629) — an in-silico prediction, not a clinical call.

INVS p.Val35Ile

c.103G>A · rs368173855 · VCV1010223

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0629 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0594%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis 2

Computational evidence

Protein change
AlphaMissense	0.0629	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -6.28	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 -0.56	GERP -3.4
Regional constraint	o/e 0.92	unconstrained · MANE · 142 kb · p 0.1 · regional, not allelic
Overall
CADD	2.174	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 0.0594% South Asian · 54/90,936 alleles

Filtering AF 0.0467% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0422%

Overall 0.00479% 77/1,607,892 alleles · ultra-rare exomes 67/1,455,710 · genomes 10/152,182 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0594%	1,684
East Asian	0.00446%	22,439
Remaining individualsnot grpmax-eligible	0.00321%	31,158
African / African-American	0.00267%	37,398
Finnishnot grpmax-eligible	0.00156%	64,010
European (non-Finnish)	0.00136%	73,401

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.Val35Ile
Coding: c.103G>A
MANE Select: NM_014425
dbSNP: rs368173855
Type: single nucleotide variant
Location: chr9:100104624 (GRCh38)
Gene constraint: LOEUF 0.941 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.76

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

Disease context

nephronophthisis 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

INVS p.Val35Ala 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-val35ile (accessed [today's date]).

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