Is VPS11 p.Leu22Pro (c.65T>C) pathogenic?

VPS11 p.Leu22Pro (c.65T>C) is classified Uncertain significance in VPS11 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-04). AlphaMissense: likely benign (0.0513); Very rare (popmax 0.00897%, amr); Associated with Inborn genetic diseases.

What condition is associated with VPS11 p.Leu22Pro (c.65T>C)?

VPS11 p.Leu22Pro (c.65T>C) is associated with Inborn genetic diseases (ClinVar).

How common is VPS11 p.Leu22Pro (c.65T>C) in the general population?

VPS11 p.Leu22Pro (c.65T>C) is very rare (popmax 0.00897%, amr) (gnomAD).

What do computational predictors say about VPS11 p.Leu22Pro (c.65T>C)?

AlphaMissense predicts likely benign (score 0.0513) — an in-silico prediction, not a clinical call.

VPS11 p.Leu22Pro

c.65T>C · VCV3468197

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0513 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00897%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0513	likely benign
SaProt	LLR -5.89	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.95	GERP 0.23, phastCons 0.32
Regional constraint	o/e 1.37	unconstrained · MANE · 101 bp · p 0.012 · regional, not allelic
Overall
CADD	18.29	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 0.00897% Admixed American · 5/55,772 alleles

Filtering AF 0.00345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0022%

Overall 0.000503% 8/1,590,186 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00897%	11,154
Remaining individualsnot grpmax-eligible	0.00162%	61,562
African / African-American	0.00134%	74,576
European (non-Finnish)	8.56e-05%	1,168,298

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: VPS11
Protein: p.Leu22Pro
Coding: c.65T>C
MANE Select: NM_021729
Type: single nucleotide variant
Location: chr11:119067888 (GRCh38)
Gene constraint: LOEUF 0.597 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.01

Full VPS11 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

VPS11 p.Ala27Pro Uncertain significance ★★ ⚠ same condition
VPS11 p.Asp14His Uncertain significance ★★ ⚠ same condition
VPS11 p.Ala250Val Uncertain significance ★ same condition
VPS11 p.Ala28Thr Uncertain significance ★ ⚠ same condition
VPS11 p.Ala388Val Uncertain significance ★ ⚠ same condition
VPS11 p.Arg772Lys Uncertain significance ★ ⚠ same condition
VPS11 p.Asn110Asp Uncertain significance ★ ⚠ same condition
VPS11 p.Asn186His Uncertain significance ★ ⚠ 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/vps11-p-leu22pro (accessed [today's date]).

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