Is VLDLR p.Arg276Pro (c.827G>C) pathogenic?

VLDLR p.Arg276Pro (c.827G>C) is classified Uncertain significance in VLDLR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-30). AlphaMissense: likely benign (0.1979); Ultra-rare (popmax 0.0223%, eas); Associated with Inborn genetic diseases.

What condition is associated with VLDLR p.Arg276Pro (c.827G>C)?

VLDLR p.Arg276Pro (c.827G>C) is associated with Inborn genetic diseases (ClinVar).

How common is VLDLR p.Arg276Pro (c.827G>C) in the general population?

VLDLR p.Arg276Pro (c.827G>C) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

What do computational predictors say about VLDLR p.Arg276Pro (c.827G>C)?

AlphaMissense predicts likely benign (score 0.1979) — an in-silico prediction, not a clinical call.

VLDLR p.Arg276Pro

c.827G>C · rs748580464 · VCV1315259

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1979 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1979	likely benign
REVEL	0.538	indeterminate
SaProt	LLR -6.21	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 0.099, phastCons 0.99
Regional constraint	o/e 1.13	unconstrained · MANE · 32 kb · p 3.3e-05 · regional, not allelic
Overall
CADD	18.53	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.0223% East Asian · 10/44,886 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00916%

Overall 0.00155% 25/1,614,052 alleles · ultra-rare exomes 23/1,461,890 · genomes 2/152,162 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0223%	4,489
Remaining individualsnot grpmax-eligible	0.0192%	5,207
Admixed American	0.00333%	30,002
European (non-Finnish)	8.47e-05%	1,180,036

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: VLDLR
Protein: p.Arg276Pro
Coding: c.827G>C
MANE Select: NM_003383
dbSNP: rs748580464
Type: single nucleotide variant
Location: chr9:2643634 (GRCh38)
Gene constraint: LOEUF 0.828 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.12 · 27 PDB
Residue 276: the ldl-receptor class a 7 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

VLDLR p.Arg276Ter Pathogenic ★ same residue
VLDLR p.Arg276= Conflicting classifications of pathogenicity ★ same residue
VLDLR p.Ala195Thr Uncertain significance ★★ ⚠ same condition
VLDLR p.Arg165His Uncertain significance ★★ ⚠ same condition
VLDLR p.Arg279Gln Uncertain significance ★★ ⚠ same condition
VLDLR p.Arg613His Uncertain significance ★★ ⚠ same condition
VLDLR p.Arg656Cys Uncertain significance ★★ ⚠ same condition
VLDLR p.Asn741Ser 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-arg276pro (accessed [today's date]).

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