Is VPS13B p.Phe366Ser (c.1097T>C) pathogenic?

VPS13B p.Phe366Ser (c.1097T>C) is classified Uncertain significance in VPS13B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-07). AlphaMissense: likely benign (0.0662); Very rare (popmax 0.00668%, eas); Associated with Inborn genetic diseases.

What condition is associated with VPS13B p.Phe366Ser (c.1097T>C)?

VPS13B p.Phe366Ser (c.1097T>C) is associated with Inborn genetic diseases, Cohen syndrome (ClinVar).

How common is VPS13B p.Phe366Ser (c.1097T>C) in the general population?

VPS13B p.Phe366Ser (c.1097T>C) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about VPS13B p.Phe366Ser (c.1097T>C)?

AlphaMissense predicts likely benign (score 0.0662) — an in-silico prediction, not a clinical call.

VPS13B p.Phe366Ser

c.1097T>C · rs543010361 · VCV1426361

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0662 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0662	likely benign
REVEL	0.072	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 0.35, phastCons 0.96
Regional constraint	o/e 0.96	unconstrained · MANE · 760 kb · p 0.015 · regional, not allelic
Overall
CADD	11.24	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 0.00668% East Asian · 3/44,878 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000248% 4/1,614,140 alleles · very rare exomes 2/1,461,882 · genomes 2/152,258 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,959
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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.Phe366Ser
Coding: c.1097T>C
MANE Select: NM_152564
dbSNP: rs543010361
Type: single nucleotide variant
Location: chr8:99121336 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI <0.01 (gnomAD)
Residue 366: 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

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

Also linked: Cohen syndrome

Similar variants

VPS13B p.Phe366= 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-phe366ser (accessed [today's date]).

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