Is LRPPRC p.Pro577Thr (c.1729C>A) pathogenic?

LRPPRC p.Pro577Thr (c.1729C>A) is classified Uncertain significance in LRPPRC (ClinVar, Single submitter, 1 submitter; last evaluated 2026-09-04). AlphaMissense: likely benign (0.192); Ultra-rare (popmax 0.036%, afr).

How common is LRPPRC p.Pro577Thr (c.1729C>A) in the general population?

LRPPRC p.Pro577Thr (c.1729C>A) is ultra-rare (popmax 0.036%, afr) (gnomAD).

What do computational predictors say about LRPPRC p.Pro577Thr (c.1729C>A)?

AlphaMissense predicts likely benign (score 0.192) — an in-silico prediction, not a clinical call.

LRPPRC p.Pro577Thr

c.1729C>A · VCV3370171

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.192 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.036%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.192	likely benign
REVEL	0.185	benign-leaning
SaProt	LLR -7.45	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 3.3	GERP -0.051, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 107 kb · p 2.9e-18 · regional, not allelic
Overall
CADD	16.76	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 0.036% African / African-American · 27/75,028 alleles

Filtering AF 0.0254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0218%

Overall 0.00174% 28/1,613,680 alleles · ultra-rare exomes 11/1,461,380 · genomes 17/152,300 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.036%	2,779
Admixed American	0.00167%	60,016

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.Pro577Thr
Coding: c.1729C>A
MANE Select: NM_133259
Type: single nucleotide variant
Location: chr2:43949608 (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

Similar variants

LRPPRC p.Pro577Leu Uncertain significance ★ ⚠ same residue
LRPPRC p.Pro577= Likely benign ★ same residue
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

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-pro577thr (accessed [today's date]).

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