Is VPS16 p.Pro46Ser (c.136C>T) pathogenic?

VPS16 p.Pro46Ser (c.136C>T) is classified Uncertain significance in VPS16 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-10). AlphaMissense: likely pathogenic (0.611); Rare (popmax 0.136%, eas); Associated with Inborn genetic diseases.

What condition is associated with VPS16 p.Pro46Ser (c.136C>T)?

VPS16 p.Pro46Ser (c.136C>T) is associated with Inborn genetic diseases (ClinVar).

How common is VPS16 p.Pro46Ser (c.136C>T) in the general population?

VPS16 p.Pro46Ser (c.136C>T) is rare (popmax 0.136%, eas) (gnomAD).

What do computational predictors say about VPS16 p.Pro46Ser (c.136C>T)?

AlphaMissense predicts likely pathogenic (score 0.611) — an in-silico prediction, not a clinical call.

VPS16 p.Pro46Ser

c.136C>T · rs201176727 · VCV3188833

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.611 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.136%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.611	likely pathogenic
REVEL	0.266	benign-leaning
SaProt	LLR -11.59	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 26 kb · p 8.4e-07 · regional, not allelic
Overall
CADD	25.6	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 0.136% East Asian · 61/44,858 alleles

Filtering AF 0.109% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0987%

Overall 0.00441% 71/1,608,420 alleles · rare exomes 59/1,456,246 · genomes 12/152,174 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.136%	735
Remaining individualsnot grpmax-eligible	0.00804%	12,442
South Asian	0.00554%	18,049

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: VPS16
Protein: p.Pro46Ser
Coding: c.136C>T
MANE Select: NM_022575
dbSNP: rs201176727
Type: single nucleotide variant
Location: chr20:2859801 (GRCh38)
Gene constraint: LOEUF 0.813 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.35 · 1 PDB

Full VPS16 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

VPS16 p.Arg129Gln Uncertain significance ★★ ⚠ same condition
VPS16 p.Arg262Trp Uncertain significance ★★ ⚠ same condition
VPS16 p.Arg273Cys Uncertain significance ★★ ⚠ same condition
VPS16 p.Arg317Cys Uncertain significance ★★ ⚠ same condition
VPS16 p.Glu297Lys Uncertain significance ★★ ⚠ same condition
VPS16 p.Glu96Lys Uncertain significance ★★ ⚠ same condition
VPS16 p.Leu66Val Uncertain significance ★★ ⚠ same condition
VPS16 p.Ser398Arg 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/vps16-p-pro46ser (accessed [today's date]).

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