Is VPS13B p.Pro441Ser (c.1321C>T) pathogenic?

VPS13B p.Pro441Ser (c.1321C>T) is classified Uncertain significance in VPS13B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-12). AlphaMissense: likely benign (0.1093); Very rare (popmax 0.0011%, sas); Associated with Cohen syndrome.

What condition is associated with VPS13B p.Pro441Ser (c.1321C>T)?

VPS13B p.Pro441Ser (c.1321C>T) is associated with Cohen syndrome (ClinVar).

How common is VPS13B p.Pro441Ser (c.1321C>T) in the general population?

VPS13B p.Pro441Ser (c.1321C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about VPS13B p.Pro441Ser (c.1321C>T)?

AlphaMissense predicts likely benign (score 0.1093) — an in-silico prediction, not a clinical call.

VPS13B p.Pro441Ser

c.1321C>T · rs1563560482 · VCV1501398

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1093 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Cohen syndrome

Computational evidence

Protein change
AlphaMissense	0.1093	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.86	GERP 0.77, phastCons 0.83
Regional constraint	o/e 0.96	unconstrained · MANE · 760 kb · p 0.015 · regional, not allelic
Overall
CADD	21.2	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,052 alleles

Overall 6.2e-05% 1/1,613,428 alleles · very rare exomes 1/1,461,380 · genomes 0/152,048 · joint denominator

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.Pro441Ser
Coding: c.1321C>T
MANE Select: NM_152564
dbSNP: rs1563560482
Type: single nucleotide variant
Location: chr8:99135033 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI <0.01 (gnomAD)
Residue 441: a UniProt-annotated variant site (in coh1); a UniProt-annotated variant site (in coh1; leads to an accumulation of liquid droplets and accelerates differentiation of adipose cells; response to insulin is abnormal)

Full VPS13B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cohen syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

VPS13B p.Pro441= Likely benign ★ 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-pro441ser (accessed [today's date]).

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