Is LRPPRC p.Ala414Pro (c.1240G>C) pathogenic?

LRPPRC p.Ala414Pro (c.1240G>C) is classified Uncertain significance in LRPPRC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-27). AlphaMissense: likely pathogenic (0.9596); Absent from gnomAD v4.1.

How common is LRPPRC p.Ala414Pro (c.1240G>C) in the general population?

LRPPRC p.Ala414Pro (c.1240G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LRPPRC p.Ala414Pro (c.1240G>C)?

AlphaMissense predicts likely pathogenic (score 0.9596) — an in-silico prediction, not a clinical call.

LRPPRC p.Ala414Pro

c.1240G>C · VCV3337253

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9596 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9596	likely pathogenic · top 3% in LRPPRC
REVEL	0.439	indeterminate
SaProt	LLR -15.04	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.3, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 107 kb · p 2.9e-18 · regional, not allelic
Overall
CADD	23.6	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: LRPPRC
Protein: p.Ala414Pro
Coding: c.1240G>C
MANE Select: NM_133259
Type: single nucleotide variant
Location: chr2:43973816 (GRCh38)
Gene constraint: LOEUF 0.808 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.35 · 2 PDB
Residue 414: an α-helix

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

Similar variants

LRPPRC c.1369+1G>C Likely pathogenic ★★ same type
LRPPRC c.1582+7A>G Likely pathogenic ★★ same type
LRPPRC c.1677+1G>A Likely pathogenic ★★ same type
LRPPRC c.1677+1G>T Likely pathogenic ★★ same type
LRPPRC c.1678-1G>A Likely pathogenic ★★ same type
LRPPRC c.1735+2T>C Likely pathogenic ★★ same type
LRPPRC c.1920+1G>T Pathogenic/Likely pathogenic ★★ same type
LRPPRC c.1965+2T>C Likely pathogenic ★★ 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/lrpprc-p-ala414pro (accessed [today's date]).

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