Is CAVIN3 p.Pro199Leu (c.596C>T) pathogenic?

CAVIN3 p.Pro199Leu (c.596C>T) is classified Uncertain significance in CAVIN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-04). AlphaMissense: likely benign (0.0978); Ultra-rare (popmax 0.0168%, nfe).

How common is CAVIN3 p.Pro199Leu (c.596C>T) in the general population?

CAVIN3 p.Pro199Leu (c.596C>T) is ultra-rare (popmax 0.0168%, nfe) (gnomAD).

What do computational predictors say about CAVIN3 p.Pro199Leu (c.596C>T)?

AlphaMissense predicts likely benign (score 0.0978) — an in-silico prediction, not a clinical call.

CAVIN3 p.Pro199Leu

c.596C>T · rs146538294 · VCV3137908

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0978 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0978	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -6.46	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 4.4	GERP 1.3, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 1,310 bp · p 0.029 · regional, not allelic
Overall
CADD	22.9	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 0.0168% European (non-Finnish) · 197/1,172,834 alleles

Filtering AF 0.0149% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0141%

Overall 0.0131% 209/1,595,546 alleles · ultra-rare exomes 194/1,443,340 · genomes 15/152,206 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0168%	5,953
Remaining individualsnot grpmax-eligible	0.0146%	6,832
African / African-American	0.0027%	36,978
Admixed American	0.0018%	55,644

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: CAVIN3
Protein: p.Pro199Leu
Coding: c.596C>T
MANE Select: NM_145040
dbSNP: rs146538294
Type: single nucleotide variant
Location: chr11:6319353 (GRCh38)
Gene constraint: LOEUF 1.958 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.11
Residue 199: the 'interaction with cav1' region; the 'disordered' region

Full CAVIN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAVIN3 p.Ala141Ser Uncertain significance ★ ⚠ same type
CAVIN3 p.Ala218Gly Uncertain significance ★ ⚠ same type
CAVIN3 p.Ala220Ser Uncertain significance ★ ⚠ same type
CAVIN3 p.Ala227Val Uncertain significance ★ ⚠ same type
CAVIN3 p.Ala249Ser Uncertain significance ★ ⚠ same type
CAVIN3 p.Ala66Thr Uncertain significance ★ ⚠ same type
CAVIN3 p.Ala94Thr Uncertain significance ★ ⚠ same type
CAVIN3 p.Ala95Val Uncertain significance ★ ⚠ same type

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/cavin3-p-pro199leu (accessed [today's date]).

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