Is VPS13B p.Pro136Ser (c.406C>T) pathogenic?

VPS13B p.Pro136Ser (c.406C>T) is classified Uncertain significance in VPS13B (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-09-08). AlphaMissense: likely pathogenic (0.8855); Very rare (popmax 0.00167%, amr); Associated with Cohen syndrome.

What condition is associated with VPS13B p.Pro136Ser (c.406C>T)?

VPS13B p.Pro136Ser (c.406C>T) is associated with Cohen syndrome (ClinVar).

How common is VPS13B p.Pro136Ser (c.406C>T) in the general population?

VPS13B p.Pro136Ser (c.406C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about VPS13B p.Pro136Ser (c.406C>T)?

AlphaMissense predicts likely pathogenic (score 0.8855) — an in-silico prediction, not a clinical call.

VPS13B p.Pro136Ser

c.406C>T · rs757950339 · VCV361037

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8855 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

Cohen syndrome

Computational evidence

Protein change
AlphaMissense	0.8855	likely pathogenic
REVEL	0.353	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 102 kb · p 2.7e-06 · regional, not allelic
Overall
CADD	23.9	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 0.00167% Admixed American · 1/59,972 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00112% 18/1,613,856 alleles · very rare exomes 16/1,461,734 · genomes 2/152,122 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,972
European (non-Finnish)	0.00144%	69,408

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.Pro136Ser
Coding: c.406C>T
MANE Select: NM_152564
dbSNP: rs757950339
Type: single nucleotide variant
Location: chr8:99096426 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI <0.01 (gnomAD)
Residue 136: 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 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-pro136ser (accessed [today's date]).

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