Is VPS13B p.Ser1964Pro (c.5890T>C) pathogenic?

VPS13B p.Ser1964Pro (c.5890T>C) is classified Conflicting classifications of pathogenicity in VPS13B (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-24). AlphaMissense: likely benign (0.078); Rare (popmax 0.101%, afr); Associated with Inborn genetic diseases.

What condition is associated with VPS13B p.Ser1964Pro (c.5890T>C)?

VPS13B p.Ser1964Pro (c.5890T>C) is associated with Inborn genetic diseases, Cohen syndrome (ClinVar).

How common is VPS13B p.Ser1964Pro (c.5890T>C) in the general population?

VPS13B p.Ser1964Pro (c.5890T>C) is rare (popmax 0.101%, afr) (gnomAD).

What do computational predictors say about VPS13B p.Ser1964Pro (c.5890T>C)?

AlphaMissense predicts likely benign (score 0.078) — an in-silico prediction, not a clinical call.

VPS13B p.Ser1964Pro

c.5890T>C · rs148704031 · VCV196921

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.078 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.101%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.078	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP 0.65, phastCons 0.99
Regional constraint	o/e 0.96	unconstrained · MANE · 760 kb · p 0.015 · regional, not allelic
Overall
CADD	16.84	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S1989P vs ClinVar S1964P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.101% African / African-American · 76/75,048 alleles

Filtering AF 0.0829% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0762%

Overall 0.00614% 99/1,613,374 alleles · rare exomes 70/1,461,034 · genomes 29/152,340 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.101%	987
Middle Eastern	0.033%	3,026
Remaining individualsnot grpmax-eligible	0.024%	4,166
South Asian	0.00439%	22,769
Admixed American	0.00167%	59,932
European (non-Finnish)	8.48e-05%	1,179,874

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: VPS13B
Protein: p.Ser1964Pro
Coding: c.5890T>C
MANE Select: NM_152564
dbSNP: rs148704031
Type: single nucleotide variant
Location: chr8:99642480 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI <0.01 (gnomAD)

Full VPS13B 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

Also linked: Cohen syndrome

Similar variants

VPS13B p.Ser1964= Uncertain significance same residue
VPS13B c.10867+1G>A Likely pathogenic ★★ same condition
VPS13B c.10868-2A>G Likely pathogenic ★★ same condition
VPS13B c.11044+1G>A Pathogenic/Likely pathogenic ★★ same condition
VPS13B c.11392+1G>T Likely pathogenic ★★ same condition
VPS13B c.11496-2A>G Pathogenic ★★ same condition
VPS13B c.11746-1G>A Pathogenic/Likely pathogenic ★★ same condition
VPS13B c.1843+1G>A 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/vps13b-p-ser1964pro (accessed [today's date]).

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