Is LRPPRC p.Pro577Leu (c.1730C>T) pathogenic?

LRPPRC p.Pro577Leu (c.1730C>T) is classified Uncertain significance in LRPPRC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-28). AlphaMissense: likely benign (0.271); Ultra-rare (popmax 0.033%, mid); Associated with Inborn genetic diseases.

What condition is associated with LRPPRC p.Pro577Leu (c.1730C>T)?

LRPPRC p.Pro577Leu (c.1730C>T) is associated with Inborn genetic diseases (ClinVar).

How common is LRPPRC p.Pro577Leu (c.1730C>T) in the general population?

LRPPRC p.Pro577Leu (c.1730C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about LRPPRC p.Pro577Leu (c.1730C>T)?

AlphaMissense predicts likely benign (score 0.271) — an in-silico prediction, not a clinical call.

LRPPRC p.Pro577Leu

c.1730C>T · VCV4623916

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.271 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.271	likely benign
REVEL	0.259	benign-leaning
SaProt	LLR -8.71	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 7.4	GERP 0.75, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 107 kb · p 2.9e-18 · regional, not allelic
Overall
CADD	21.4	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 0.033% Middle Eastern · 2/6,060 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00812%

Overall 0.00707% 114/1,613,472 alleles · ultra-rare exomes 104/1,461,236 · genomes 10/152,236 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,030
African / African-American	0.0173%	5,769
South Asian	0.0132%	7,584
Remaining individualsnot grpmax-eligible	0.008%	12,498
Finnishnot grpmax-eligible	0.00781%	12,801
European (non-Finnish)	0.00636%	15,727
East Asian	0.00223%	44,872
Admixed American	0.00167%	60,002

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.Pro577Leu
Coding: c.1730C>T
MANE Select: NM_133259
Type: single nucleotide variant
Location: chr2:43949607 (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 p.Pro577Thr Uncertain significance ★ ⚠ same residue
LRPPRC p.Pro577= Likely benign ★ same residue
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

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-pro577leu (accessed [today's date]).

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