Is LRPPRC p.Lys226= (c.678G>A) pathogenic?

LRPPRC p.Lys226= (c.678G>A) is classified Likely benign in LRPPRC (ClinVar, Single submitter, 2 submitters; last evaluated 2026-01-18). Very rare (popmax 0.00017%, nfe); Associated with congenital lactic acidosis, Saguenay-Lac-Saint-Jean type.

What condition is associated with LRPPRC p.Lys226= (c.678G>A)?

LRPPRC p.Lys226= (c.678G>A) is associated with congenital lactic acidosis, Saguenay-Lac-Saint-Jean type (ClinVar).

How common is LRPPRC p.Lys226= (c.678G>A) in the general population?

LRPPRC p.Lys226= (c.678G>A) is very rare (popmax 0.00017%, nfe) (gnomAD).

LRPPRC p.Lys226=

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.678G>A · rs1674047403 · VCV1565769

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.57	GERP -0.68, phastCons 1
Overall
CADD	9.207	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,177,348 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,458,916 alleles · very rare

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.Lys226=
Coding: c.678G>A
MANE Select: NM_133259
dbSNP: rs1674047403
Type: single nucleotide variant
Location: chr2:43976202 (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 226: a modified residue (n6-acetyllysine); an α-helix

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.Lys226Glu Uncertain significance ⚠ 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
LRPPRC c.1965+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-lys226 (accessed [today's date]).

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