Is INVS p.Ala650Pro (c.1948G>C) pathogenic?

INVS p.Ala650Pro (c.1948G>C) is classified Benign/Likely benign in INVS (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-09). AlphaMissense: likely benign (0.0757); Rare (popmax 0.438%, nfe); Associated with kidney disorder.

What condition is associated with INVS p.Ala650Pro (c.1948G>C)?

INVS p.Ala650Pro (c.1948G>C) is associated with kidney disorder, nephronophthisis 2, nephronophthisis (ClinVar).

How common is INVS p.Ala650Pro (c.1948G>C) in the general population?

INVS p.Ala650Pro (c.1948G>C) is rare (popmax 0.438%, nfe) (gnomAD).

What do computational predictors say about INVS p.Ala650Pro (c.1948G>C)?

AlphaMissense predicts likely benign (score 0.0757) — an in-silico prediction, not a clinical call.

INVS p.Ala650Pro

c.1948G>C · rs147452898 · VCV95596

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0757 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.438%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

kidney disorder

Computational evidence

Protein change
AlphaMissense	0.0757	likely benign
REVEL	0.233	benign-leaning
SaProt	LLR -5.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.8	GERP -1.9, phastCons 0.9
Regional constraint	o/e 0.99	unconstrained · MANE · 16 kb · p 0.9 · regional, not allelic
Overall
CADD	12.55	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.438% European (non-Finnish) · 5,164/1,180,004 alleles

Filtering AF 0.428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.424%

Overall 0.421% 6,788/1,614,130 alleles · rare exomes 6,217/1,461,770 · genomes 571/152,360 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.92%	52
European (non-Finnish)grpmax	0.438%	229
Remaining individualsnot grpmax-eligible	0.355%	282
Amishnot grpmax-eligible	0.329%	304
Admixed American	0.108%	923
Middle Eastern	0.099%	1,010
African / African-American	0.0719%	1,390
South Asian	0.0472%	2,118
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,594

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala650Pro
Coding: c.1948G>C
MANE Select: NM_014425
dbSNP: rs147452898
Type: single nucleotide variant
Location: chr9:100284483 (GRCh38)
Gene constraint: LOEUF 0.941 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.76
Residue 650: the 'disordered' region

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

Disease context

kidney disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 2 nephronophthisis

Similar variants

INVS p.Ala650= Likely benign ★ 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-ala650pro (accessed [today's date]).

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