Is CAVIN3 p.Leu122Pro (c.365T>C) pathogenic?

CAVIN3 p.Leu122Pro (c.365T>C) is classified Uncertain significance in CAVIN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-21). AlphaMissense: likely pathogenic (0.6365); Ultra-rare (popmax 0.0814%, amr).

How common is CAVIN3 p.Leu122Pro (c.365T>C) in the general population?

CAVIN3 p.Leu122Pro (c.365T>C) is ultra-rare (popmax 0.0814%, amr) (gnomAD).

What do computational predictors say about CAVIN3 p.Leu122Pro (c.365T>C)?

AlphaMissense predicts likely pathogenic (score 0.6365) — an in-silico prediction, not a clinical call.

CAVIN3 p.Leu122Pro

c.365T>C · VCV3485539

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6365 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0814%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6365	likely pathogenic · top 10% in CAVIN3
REVEL	0.45	indeterminate
SaProt	LLR -7.06	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 1,310 bp · p 0.029 · regional, not allelic
Overall
CADD	32.0	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 0.0814% Admixed American · 48/58,974 alleles

Filtering AF 0.063% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0565%

Overall 0.00333% 53/1,589,644 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0814%	1,229
Remaining individualsnot grpmax-eligible	0.00323%	30,954
European (non-Finnish)	0.000255%	392,109

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.Leu122Pro
Coding: c.365T>C
MANE Select: NM_145040
Type: single nucleotide variant
Location: chr11:6320112 (GRCh38)
Gene constraint: LOEUF 1.958 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.11

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-leu122pro (accessed [today's date]).

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