Is VLDLR p.Arg231His (c.692G>A) pathogenic?

VLDLR p.Arg231His (c.692G>A) is classified Uncertain significance in VLDLR (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-26). AlphaMissense: likely benign (0.0686); Ultra-rare (popmax 0.0164%, mid); Associated with cerebellar ataxia, intellectual disability, and dysequilibrium.

What condition is associated with VLDLR p.Arg231His (c.692G>A)?

VLDLR p.Arg231His (c.692G>A) is associated with cerebellar ataxia, intellectual disability, and dysequilibrium, cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1 (ClinVar).

How common is VLDLR p.Arg231His (c.692G>A) in the general population?

VLDLR p.Arg231His (c.692G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

How is Dysequilibrium syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about VLDLR p.Arg231His (c.692G>A)?

AlphaMissense predicts likely benign (score 0.0686) — an in-silico prediction, not a clinical call.

VLDLR p.Arg231His

c.692G>A · rs767529669 · VCV366364

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0686 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cerebellar ataxia, intellectual disability, and dysequilibrium

Computational evidence

Protein change
AlphaMissense	0.0686	likely benign
REVEL	0.254	benign-leaning
SaProt	LLR -7.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 1.1, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 32 kb · p 3.3e-05 · regional, not allelic
Overall
CADD	23.0	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.00254% 41/1,613,982 alleles · ultra-rare exomes 38/1,461,842 · genomes 3/152,140 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
South Asian	0.011%	9,108
Remaining individualsnot grpmax-eligible	0.0064%	15,621
East Asian	0.00223%	44,890
European (non-Finnish)	0.00203%	49,168
African / African-American	0.00134%	74,906

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.Arg231His
Coding: c.692G>A
MANE Select: NM_003383
dbSNP: rs767529669
Type: single nucleotide variant
Location: chr9:2643403 (GRCh38)
Gene constraint: LOEUF 0.828 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.12 · 27 PDB
Residue 231: the ldl-receptor class a 5 domain

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

Disease context

cerebellar ataxia, intellectual disability, and dysequilibrium — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Dysequilibrium syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal
Prevalence: <1 / 1 000 000 (Worldwide)

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-arg231his (accessed [today's date]).

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