Is LRPPRC p.Arg541Ser (c.1623A>T) pathogenic?

LRPPRC p.Arg541Ser (c.1623A>T) is classified Uncertain significance in LRPPRC (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: likely pathogenic (0.7905); Ultra-rare (popmax 0.0165%, mid); Associated with congenital lactic acidosis, Saguenay-Lac-Saint-Jean type.

What condition is associated with LRPPRC p.Arg541Ser (c.1623A>T)?

LRPPRC p.Arg541Ser (c.1623A>T) is associated with congenital lactic acidosis, Saguenay-Lac-Saint-Jean type (ClinVar).

How common is LRPPRC p.Arg541Ser (c.1623A>T) in the general population?

LRPPRC p.Arg541Ser (c.1623A>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about LRPPRC p.Arg541Ser (c.1623A>T)?

AlphaMissense predicts likely pathogenic (score 0.7905) — an in-silico prediction, not a clinical call.

LRPPRC p.Arg541Ser

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.1623A>T · rs1673163352 · VCV898508

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7905 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.7905	likely pathogenic
REVEL	0.393	indeterminate
SaProt	LLR -6.28	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 0.075, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 107 kb · p 2.9e-18 · regional, not allelic
Overall
CADD	20.4	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 0.0165% Middle Eastern · 1/6,056 alleles

Overall 6.84e-05% 1/1,461,198 alleles · ultra-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.Arg541Ser
Coding: c.1623A>T
MANE Select: NM_133259
dbSNP: rs1673163352
Type: single nucleotide variant
Location: chr2:43957411 (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 541: 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 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
LRPPRC c.2505-2A>T 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-arg541ser (accessed [today's date]).

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