Is VPS13B p.Ser684Phe (c.2051C>T) pathogenic?

VPS13B p.Ser684Phe (c.2051C>T) is classified Conflicting classifications of pathogenicity in VPS13B (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-11-05). AlphaMissense: likely benign (0.1287); Ultra-rare (popmax 0.024%, afr); Associated with Cohen syndrome.

What condition is associated with VPS13B p.Ser684Phe (c.2051C>T)?

VPS13B p.Ser684Phe (c.2051C>T) is associated with Cohen syndrome (ClinVar).

How common is VPS13B p.Ser684Phe (c.2051C>T) in the general population?

VPS13B p.Ser684Phe (c.2051C>T) is ultra-rare (popmax 0.024%, afr) (gnomAD).

What do computational predictors say about VPS13B p.Ser684Phe (c.2051C>T)?

AlphaMissense predicts likely benign (score 0.1287) — an in-silico prediction, not a clinical call.

VPS13B p.Ser684Phe

c.2051C>T · rs367999029 · VCV971372

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1287 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.024%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Cohen syndrome

Computational evidence

Protein change
AlphaMissense	0.1287	likely benign
REVEL	0.237	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 2.2	GERP 1.9, phastCons 0.91
Regional constraint	o/e 0.96	unconstrained · MANE · 760 kb · p 0.015 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.024% African / African-American · 18/74,950 alleles

Filtering AF 0.0155% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.00112% 18/1,613,958 alleles · ultra-rare exomes 10/1,461,712 · genomes 8/152,246 · 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.Ser684Phe
Coding: c.2051C>T
MANE Select: NM_152564
dbSNP: rs367999029
Type: single nucleotide variant
Location: chr8:99156586 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI <0.01 (gnomAD)
Residue 684: 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 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
VPS13B c.2516-2A>G 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-ser684phe (accessed [today's date]).

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