Is LRPPRC p.Arg99Cys (c.295C>T) pathogenic?

LRPPRC p.Arg99Cys (c.295C>T) is classified Uncertain significance in LRPPRC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-04-22). AlphaMissense: likely benign (0.2828); Ultra-rare (popmax 0.0336%, sas); Associated with congenital lactic acidosis, Saguenay-Lac-Saint-Jean type.

What condition is associated with LRPPRC p.Arg99Cys (c.295C>T)?

LRPPRC p.Arg99Cys (c.295C>T) is associated with congenital lactic acidosis, Saguenay-Lac-Saint-Jean type (ClinVar).

How common is LRPPRC p.Arg99Cys (c.295C>T) in the general population?

LRPPRC p.Arg99Cys (c.295C>T) is ultra-rare (popmax 0.0336%, sas) (gnomAD).

What do computational predictors say about LRPPRC p.Arg99Cys (c.295C>T)?

AlphaMissense predicts likely benign (score 0.2828) — an in-silico prediction, not a clinical call.

LRPPRC p.Arg99Cys

Q: How is Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.295C>T · rs771473230 · VCV1029067

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2828 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0336%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital lactic acidosis, Saguenay-Lac-Saint-Jean type

Computational evidence

Protein change
AlphaMissense	0.2828	likely benign
REVEL	0.39	indeterminate
SaProt	LLR -6.33	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.54, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 107 kb · p 2.9e-18 · regional, not allelic
Overall
CADD	26.8	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 0.0336% South Asian · 29/86,200 alleles

Filtering AF 0.024% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0208%

Overall 0.00429% 68/1,583,490 alleles · ultra-rare exomes 59/1,431,430 · genomes 9/152,060 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0336%	2,972
African / African-American	0.0123%	8,134
East Asian	0.0045%	22,229
Finnishnot grpmax-eligible	0.00314%	31,800
European (non-Finnish)	0.00223%	44,871

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.Arg99Cys
Coding: c.295C>T
MANE Select: NM_133259
dbSNP: rs771473230
Type: single nucleotide variant
Location: chr2:43982289 (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

congenital lactic acidosis, Saguenay-Lac-Saint-Jean type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

LRPPRC p.Arg99His Uncertain significance ★ ⚠ same residue
LRPPRC p.Arg99= Likely benign ★ same residue
LRPPRC c.1369+1G>C Likely pathogenic ★★ same condition
LRPPRC c.1582+7A>G Likely pathogenic ★★ same condition
LRPPRC c.1677+1G>A Likely pathogenic ★★ same condition
LRPPRC c.1677+1G>T Likely pathogenic ★★ same condition
LRPPRC c.1678-1G>A Likely pathogenic ★★ same condition
LRPPRC c.1735+2T>C Likely pathogenic ★★ 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-arg99cys (accessed [today's date]).

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