Is INVS p.Thr458= (c.1374C>A) pathogenic?

INVS p.Thr458= (c.1374C>A) is classified Conflicting classifications of pathogenicity in INVS (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-10-20). Rare (popmax 0.317%, eas); Associated with nephronophthisis.

What condition is associated with INVS p.Thr458= (c.1374C>A)?

INVS p.Thr458= (c.1374C>A) is associated with nephronophthisis, nephronophthisis 2 (ClinVar).

How common is INVS p.Thr458= (c.1374C>A) in the general population?

INVS p.Thr458= (c.1374C>A) is rare (popmax 0.317%, eas) (gnomAD).

How is Nephronophthisis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

INVS p.Thr458=

c.1374C>A · rs114912725 · VCV700245

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.317%, eas)

Conditions

nephronophthisis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.75	GERP -1.1, phastCons 0.003
Overall
CADD	4.354	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.317% East Asian · 142/44,864 alleles

Filtering AF 0.274% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.258%

Overall 0.0108% 174/1,613,888 alleles · rare exomes 155/1,461,702 · genomes 19/152,186 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.317%	316
South Asian	0.0275%	3,643
Remaining individualsnot grpmax-eligible	0.0048%	20,834
European (non-Finnish)	0.000339%	294,966

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.Thr458=
Coding: c.1374C>A
MANE Select: NM_014425
dbSNP: rs114912725
Type: single nucleotide variant
Location: chr9:100253046 (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 — 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 p.Thr458Ser 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-thr458 (accessed [today's date]).

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