Is LRP12 p.Arg330Cys (c.988C>T) pathogenic?

LRP12 p.Arg330Cys (c.988C>T) is classified Uncertain significance in LRP12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-22). AlphaMissense: ambiguous (0.4484); Very rare (popmax 0.00334%, amr); Associated with Inborn genetic diseases.

What condition is associated with LRP12 p.Arg330Cys (c.988C>T)?

LRP12 p.Arg330Cys (c.988C>T) is associated with Inborn genetic diseases (ClinVar).

How common is LRP12 p.Arg330Cys (c.988C>T) in the general population?

LRP12 p.Arg330Cys (c.988C>T) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about LRP12 p.Arg330Cys (c.988C>T)?

AlphaMissense predicts ambiguous (score 0.4484) — an in-silico prediction, not a clinical call.

LRP12 p.Arg330Cys

c.988C>T · VCV3868139

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4484 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4484	ambiguous
REVEL	0.376	indeterminate
SaProt	LLR -10.71	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 18 kb · p 1.2e-07 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 0.00334% Admixed American · 2/59,940 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000682% 11/1,613,396 alleles · very rare exomes 10/1,461,310 · genomes 1/152,086 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,784
Admixed Americangrpmax	0.00334%	29,970
African / African-American	0.00267%	37,432
South Asian	0.0011%	90,950
European (non-Finnish)	0.000339%	294,951

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: LRP12
Protein: p.Arg330Cys
Coding: c.988C>T
MANE Select: NM_013437
Type: single nucleotide variant
Location: chr8:104497564 (GRCh38)
Gene constraint: LOEUF 0.291 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.10
Residue 330: the cub 2 domain

Full LRP12 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

LRP12 p.Arg330His Uncertain significance ★ ⚠ same residue
LRP12 p.Arg732Cys Uncertain significance ★★ ⚠ same condition
LRP12 p.Ala204Gly Uncertain significance ★ ⚠ same condition
LRP12 p.Ala2Val Uncertain significance ★ ⚠ same condition
LRP12 p.Ala554Ser Uncertain significance ★ ⚠ same condition
LRP12 p.Ala684Val Uncertain significance ★ ⚠ same condition
LRP12 p.Ala82Thr Uncertain significance ★ ⚠ same condition
LRP12 p.Arg102Ser 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/lrp12-p-arg330cys (accessed [today's date]).

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