Is VLDLR p.Cys72Arg (c.214T>C) pathogenic?

VLDLR p.Cys72Arg (c.214T>C) is classified Uncertain significance in VLDLR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-11). AlphaMissense: likely pathogenic (0.9663); Absent from gnomAD v4.1.

How common is VLDLR p.Cys72Arg (c.214T>C) in the general population?

VLDLR p.Cys72Arg (c.214T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about VLDLR p.Cys72Arg (c.214T>C)?

AlphaMissense predicts likely pathogenic (score 0.9663) — an in-silico prediction, not a clinical call.

VLDLR p.Cys72Arg

c.214T>C · VCV4881555

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9663 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9663	likely pathogenic · top 9% in VLDLR
REVEL	0.971	strongly pathogenic-leaning
SaProt	LLR -13.24	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 32 kb · p 3.3e-05 · regional, not allelic
Overall
CADD	29.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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.Cys72Arg
Coding: c.214T>C
MANE Select: NM_003383
Type: single nucleotide variant
Location: chr9:2639870 (GRCh38)
Gene constraint: LOEUF 0.828 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.12 · 27 PDB
Residue 72: a disulfide bond; the ldl-receptor class a 2 domain

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

Similar variants

VLDLR c.2252-2A>C Likely pathogenic ★★ same type
VLDLR c.449-2A>T Likely pathogenic ★★ same type
VLDLR c.83-1G>A Pathogenic/Likely pathogenic ★★ same type
VLDLR p.Arg279Ter Pathogenic ★★ same type
VLDLR p.Arg301Ter Pathogenic ★★ same type
VLDLR p.Trp529Ter Pathogenic ★★ same type
VLDLR c.-154C>G Uncertain significance ★★ same type
VLDLR c.-392C>T Uncertain significance ★★ same type

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-cys72arg (accessed [today's date]).

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