VPS35L

Chr 16AR

VPS35 endosomal protein sorting factor like

Also known as: C16orf62, EC97, RTSC3

NCBI Gene: 57020 ENSG00000103544 UniProt: Q7Z3J2 OMIM: 618981

The protein acts as a component of the retriever complex, which is essential for endosomal cargo retrieval and recycling, including transport of cell surface proteins involved in cell migration, adhesion, and signaling. Mutations cause Ritscher-Schinzel syndrome, which is inherited in an autosomal recessive pattern and typically presents in early childhood with characteristic craniofacial features, cardiac defects, and intellectual disability. This gene is highly constrained against loss-of-function variants (LOEUF 0.573), indicating that complete loss of protein function is likely not tolerated.

OMIM ResearchSummary from RefSeq, UniProt

Involved in Golgi to plasma membrane transport and endocytic recycling. Located in endosome. Implicated in Ritscher-Schinzel syndrome. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

ARLOEUF 0.571 OMIM phenotype

Clinical Summary— VPS35L

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

7 unique Pathogenic / Likely Pathogenic· 21 VUS of 71 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.57LOEUF

pLI 0.000

Z-score 4.31

OE 0.41 (0.30–0.57)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.69Z-score

OE missense 0.92 (0.86–0.99)

562 obs / 610.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.41 (0.30–0.57)

0≤0.351.4

Missense OE?0.92 (0.86–0.99)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 26 / 62.9Missense obs/exp: 562 / 610.1Syn Z: 0.16

ClinVar Variant Classifications

71 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic3

VUS21

Likely Benign8

Benign4

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	2	0	0	4
Likely Pathogenic	2	1	0	0	3
VUS	1	17	3	0	21
Likely Benign	0	0	2	6	8
Benign	0	1	2	1	4
Total	5	21	7	7	40

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

15 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap VPS35L — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →