Is VPS13B p.Pro54= (c.162A>G) pathogenic?

VPS13B p.Pro54= (c.162A>G) is classified Likely benign in VPS13B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-27). Ultra-rare (popmax 0.0134%, sas); Associated with Cohen syndrome.

What condition is associated with VPS13B p.Pro54= (c.162A>G)?

VPS13B p.Pro54= (c.162A>G) is associated with Cohen syndrome (ClinVar).

How common is VPS13B p.Pro54= (c.162A>G) in the general population?

VPS13B p.Pro54= (c.162A>G) is ultra-rare (popmax 0.0134%, sas) (gnomAD).

VPS13B p.Pro54=

c.162A>G · rs747961838 · VCV437233

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, sas)

Conditions

Cohen syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.73	GERP -1, phastCons 0.95
Overall
CADD	9.907	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% South Asian · 12/89,866 alleles

Filtering AF 0.0077% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.006%

Overall 0.000871% 14/1,606,788 alleles · ultra-rare exomes 13/1,454,646 · genomes 1/152,142 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0134%	7,489
African / African-American	0.00134%	74,846
European (non-Finnish)	8.5e-05%	1,175,906

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.Pro54=
Coding: c.162A>G
MANE Select: NM_152564
dbSNP: rs747961838
Type: single nucleotide variant
Location: chr8:99038437 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI <0.01 (gnomAD)
Residue 54: the chorein n-terminal domain; a UniProt-annotated variant site (in coh1)

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.Pro54Ser Uncertain significance ★★ ⚠ same residue
VPS13B p.Pro54Leu 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

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-pro54 (accessed [today's date]).

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