Is LRPPRC p.Cys484Arg (c.1450T>C) pathogenic?

LRPPRC p.Cys484Arg (c.1450T>C) is classified Conflicting classifications of pathogenicity in LRPPRC (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-01). AlphaMissense: ambiguous (0.4565); Ultra-rare (popmax 0.0495%, mid); Associated with Inborn genetic diseases.

What condition is associated with LRPPRC p.Cys484Arg (c.1450T>C)?

LRPPRC p.Cys484Arg (c.1450T>C) is associated with Inborn genetic diseases (ClinVar).

How common is LRPPRC p.Cys484Arg (c.1450T>C) in the general population?

LRPPRC p.Cys484Arg (c.1450T>C) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about LRPPRC p.Cys484Arg (c.1450T>C)?

AlphaMissense predicts ambiguous (score 0.4565) — an in-silico prediction, not a clinical call.

LRPPRC p.Cys484Arg

c.1450T>C · rs756499243 · VCV2144092

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4565 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4565	ambiguous
REVEL	0.109	moderately benign-leaning
SaProt	LLR -16.16	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -4.2, phastCons 0.073
Regional constraint	o/e 1.21	unconstrained · MANE · 107 kb · p 2.9e-18 · regional, not allelic
Overall
CADD	7.78	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

Grpmax group 0.0495% Middle Eastern · 3/6,060 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00718%

Overall 0.00124% 20/1,612,224 alleles · ultra-rare exomes 20/1,459,866 · genomes 0/152,358 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,020
South Asian	0.00439%	22,759
Remaining individualsnot grpmax-eligible	0.0032%	31,217
East Asian	0.00223%	44,862
European (non-Finnish)	0.000849%	117,835

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: LRPPRC
Protein: p.Cys484Arg
Coding: c.1450T>C
MANE Select: NM_133259
dbSNP: rs756499243
Type: single nucleotide variant
Location: chr2:43963626 (GRCh38)
Gene constraint: LOEUF 0.808 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.35 · 2 PDB

Full LRPPRC 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

LRPPRC c.1369+5G>A Uncertain significance ★★ same condition
LRPPRC p.Ala1093Thr Uncertain significance ★★ ⚠ same condition
LRPPRC p.Ala1360Ser Uncertain significance ★★ ⚠ same condition
LRPPRC p.Ala37Ser Uncertain significance ★★ ⚠ same condition
LRPPRC p.Ala417Thr Uncertain significance ★★ ⚠ same condition
LRPPRC p.Ala516Val Uncertain significance ★★ ⚠ same condition
LRPPRC p.Ala997Thr Uncertain significance ★★ ⚠ same condition
LRPPRC p.Arg1109Cys 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/lrpprc-p-cys484arg (accessed [today's date]).

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