Is LRPPRC p.His643Arg (c.1928A>G) pathogenic?

LRPPRC p.His643Arg (c.1928A>G) is classified Conflicting classifications of pathogenicity in LRPPRC (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0766); Rare (popmax 0.933%, mid); Associated with congenital lactic acidosis, Saguenay-Lac-Saint-Jean type.

What condition is associated with LRPPRC p.His643Arg (c.1928A>G)?

LRPPRC p.His643Arg (c.1928A>G) is associated with congenital lactic acidosis, Saguenay-Lac-Saint-Jean type (ClinVar).

How common is LRPPRC p.His643Arg (c.1928A>G) in the general population?

LRPPRC p.His643Arg (c.1928A>G) is rare (popmax 0.933%, mid) (gnomAD).

What do computational predictors say about LRPPRC p.His643Arg (c.1928A>G)?

AlphaMissense predicts likely benign (score 0.0766) — an in-silico prediction, not a clinical call.

LRPPRC p.His643Arg

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.1928A>G · rs148575027 · VCV214589

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0766 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.933%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.0766	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -1.79	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 0.18	GERP -2
Regional constraint	o/e 1.21	unconstrained · MANE · 107 kb · p 2.9e-18 · regional, not allelic
Overall
CADD	6.794	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.933% Middle Eastern · 56/6,004 alleles

Filtering AF 0.738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.667%

Overall 0.066% 1,049/1,588,248 alleles · rare exomes 935/1,436,084 · genomes 114/152,164 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.933%	107
Ashkenazi Jewishnot grpmax-eligible	0.364%	275
Remaining individualsnot grpmax-eligible	0.13%	771
Admixed American	0.0918%	1,090
European (non-Finnish)	0.0606%	1,650
South Asian	0.0331%	3,017
African / African-American	0.0188%	5,320
Finnishnot grpmax-eligible	0.00937%	10,667

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.His643Arg
Coding: c.1928A>G
MANE Select: NM_133259
dbSNP: rs148575027
Type: single nucleotide variant
Location: chr2:43947768 (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 643: 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.His643= Conflicting classifications of pathogenicity ★ same residue
LRPPRC p.His643Pro 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

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-his643arg (accessed [today's date]).

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