Is LRPPRC p.Val657fs (c.1970_1971del) pathogenic?

LRPPRC p.Val657fs (c.19701971del) is classified Likely pathogenic in LRPPRC (ClinVar, No assertion criteria, 1 submitter; last evaluated 2017-08-25). Very rare (popmax 0.000182%, nfe); Associated with congenital lactic acidosis, Saguenay-Lac-Saint-Jean type.

What condition is associated with LRPPRC p.Val657fs (c.1970_1971del)?

LRPPRC p.Val657fs (c.1970_1971del) is associated with congenital lactic acidosis, Saguenay-Lac-Saint-Jean type (ClinVar).

How common is LRPPRC p.Val657fs (c.1970_1971del) in the general population?

LRPPRC p.Val657fs (c.1970_1971del) is very rare (popmax 0.000182%, nfe) (gnomAD).

LRPPRC p.Val657fs

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.1970_1971del · rs1553403879 · VCV553475

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000182%, 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.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 20 of 38
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.3	GERP 0.52, phastCons 0.95

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000182% European (non-Finnish) · 2/1,100,588 alleles

Filtering AF 3e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000131% 2/1,525,618 alleles · very rare exomes 2/1,373,610 · genomes 0/152,008 · joint denominator

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.Val657fs
Coding: c.1970_1971del
MANE Select: NM_133259
dbSNP: rs1553403879
Type: Microsatellite
Location: chr2:43947365 (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.Lys909del Pathogenic/Likely pathogenic ★★ same condition
LRPPRC p.Leu1289del Uncertain significance ★★ same condition
LRPPRC c.2630-5_2630-2del Likely pathogenic ★ same condition
LRPPRC p.Glu1002fs Likely pathogenic ★ same condition
LRPPRC p.Leu153fs Likely pathogenic ★ same condition
LRPPRC p.Leu228fs Likely pathogenic ★ same condition
LRPPRC p.Lys1332fs Likely pathogenic ★ same condition
LRPPRC c.865-10CT[2] Likely benign ★ 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-val657fs (accessed [today's date]).

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