Is VPS13B p.Phe2011Val (c.6031T>G) pathogenic?

VPS13B p.Phe2011Val (c.6031T>G) is classified Uncertain significance in VPS13B (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-05-04). AlphaMissense: likely pathogenic (0.7333); Ultra-rare (popmax 0.01%, amr); Associated with Cohen syndrome.

What condition is associated with VPS13B p.Phe2011Val (c.6031T>G)?

VPS13B p.Phe2011Val (c.6031T>G) is associated with Cohen syndrome (ClinVar).

How common is VPS13B p.Phe2011Val (c.6031T>G) in the general population?

VPS13B p.Phe2011Val (c.6031T>G) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about VPS13B p.Phe2011Val (c.6031T>G)?

AlphaMissense predicts likely pathogenic (score 0.7333) — an in-silico prediction, not a clinical call.

VPS13B p.Phe2011Val

c.6031T>G · rs534890892 · VCV1060639

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7333 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Conditions

Cohen syndrome

Computational evidence

Protein change
AlphaMissense	0.7333	likely pathogenic
REVEL	0.504	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 760 kb · p 0.015 · regional, not allelic
Overall
CADD	26.1	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 F2036V vs ClinVar F2011V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/59,936 alleles

Filtering AF 0.00429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00321%

Overall 0.00378% 61/1,613,234 alleles · ultra-rare exomes 57/1,460,970 · genomes 4/152,264 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,989
European (non-Finnish)	0.00458%	21,847
African / African-American	0.00133%	75,030

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.Phe2011Val
Coding: c.6031T>G
MANE Select: NM_152564
dbSNP: rs534890892
Type: single nucleotide variant
Location: chr8:99661476 (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

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-phe2011val (accessed [today's date]).

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