Is VLDLR p.Cys706Phe (c.2117G>T) pathogenic?

VLDLR p.Cys706Phe (c.2117G>T) is classified Pathogenic in VLDLR (ClinVar, Single submitter, 2 submitters; last evaluated 2024-10-04). AlphaMissense: likely pathogenic (0.9295); Absent from gnomAD v4.1; Associated with Cerebellar hypoplasia.

What condition is associated with VLDLR p.Cys706Phe (c.2117G>T)?

VLDLR p.Cys706Phe (c.2117G>T) is associated with Cerebellar hypoplasia, cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1 (ClinVar).

How common is VLDLR p.Cys706Phe (c.2117G>T) in the general population?

VLDLR p.Cys706Phe (c.2117G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about VLDLR p.Cys706Phe (c.2117G>T)?

AlphaMissense predicts likely pathogenic (score 0.9295) — an in-silico prediction, not a clinical call.

VLDLR p.Cys706Phe

c.2117G>T · rs397514750 · VCV64373

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9295 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cerebellar hypoplasia

Computational evidence

Protein change
AlphaMissense	0.9295	likely pathogenic ✓ concordant with ClinVar
REVEL	0.958	strongly pathogenic-leaning
SaProt	LLR -12.84	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 32 kb · p 3.3e-05 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: VLDLR
Protein: p.Cys706Phe
Coding: c.2117G>T
MANE Select: NM_003383
dbSNP: rs397514750
Type: single nucleotide variant
Location: chr9:2650382 (GRCh38)
Gene constraint: LOEUF 0.828 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.12 · 27 PDB
Residue 706: the egf-like 3 domain; a disulfide bond

Full VLDLR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cerebellar hypoplasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1

Similar variants

VLDLR c.2252-2A>C Likely pathogenic ★★ same condition
VLDLR c.449-2A>T Likely pathogenic ★★ same condition
VLDLR c.83-1G>A Pathogenic/Likely pathogenic ★★ same condition
VLDLR p.Arg279Ter Pathogenic ★★ same condition
VLDLR p.Arg301Ter Pathogenic ★★ same condition
VLDLR c.-154C>G Uncertain significance ★★ same condition
VLDLR c.-392C>T Uncertain significance ★★ same condition
VLDLR c.*48C>T Uncertain significance ★★ 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/vldlr-p-cys706phe (accessed [today's date]).

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