Is INVS p.Ala66= (c.198T>C) pathogenic?

INVS p.Ala66= (c.198T>C) is classified Conflicting classifications of pathogenicity in INVS (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-30). Ultra-rare (popmax 0.0493%, afr); Associated with nephronophthisis.

What condition is associated with INVS p.Ala66= (c.198T>C)?

INVS p.Ala66= (c.198T>C) is associated with nephronophthisis (ClinVar).

How common is INVS p.Ala66= (c.198T>C) in the general population?

INVS p.Ala66= (c.198T>C) is ultra-rare (popmax 0.0493%, afr) (gnomAD).

How is Nephronophthisis inherited?

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

INVS p.Ala66=

c.198T>C · rs150557072 · VCV502574

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, afr)

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 -0.46	GERP -1.4, phastCons 0.14
Overall
CADD	8.036	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0493% African / African-American · 37/75,058 alleles

Filtering AF 0.0368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0323%

Overall 0.00235% 38/1,614,166 alleles · ultra-rare exomes 19/1,461,836 · genomes 19/152,330 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0493%	2,029
Remaining individualsnot grpmax-eligible	0.0016%	62,506

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.Ala66=
Coding: c.198T>C
MANE Select: NM_014425
dbSNP: rs150557072
Type: single nucleotide variant
Location: chr9:100126474 (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

For Nephronophthisis (Orphanet):

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

Similar variants

INVS p.Ala66Val Uncertain significance ★★ ⚠ same residue
INVS p.Ala66Thr 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

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-ala66 (accessed [today's date]).

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