Is LRPPRC p.Ala3Ser (c.7G>T) pathogenic?

LRPPRC p.Ala3Ser (c.7G>T) is classified Conflicting classifications of pathogenicity in LRPPRC (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2022-08-22). AlphaMissense: likely benign (0.149); Ultra-rare (popmax 0.0781%, afr); Associated with congenital lactic acidosis, Saguenay-Lac-Saint-Jean type.

What condition is associated with LRPPRC p.Ala3Ser (c.7G>T)?

LRPPRC p.Ala3Ser (c.7G>T) is associated with congenital lactic acidosis, Saguenay-Lac-Saint-Jean type (ClinVar).

How common is LRPPRC p.Ala3Ser (c.7G>T) in the general population?

LRPPRC p.Ala3Ser (c.7G>T) is ultra-rare (popmax 0.0781%, afr) (gnomAD).

What do computational predictors say about LRPPRC p.Ala3Ser (c.7G>T)?

AlphaMissense predicts likely benign (score 0.149) — an in-silico prediction, not a clinical call.

LRPPRC p.Ala3Ser

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.7G>T · rs200686732 · VCV1698663

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.149 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0781%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.149	likely benign
REVEL	0.135	moderately benign-leaning
SaProt	LLR -7.72	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 0.83	GERP -0.73, phastCons 0.65
Regional constraint	o/e 1.21	unconstrained · MANE · 107 kb · p 2.9e-18 · regional, not allelic
Overall
CADD	16.77	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 0.0781% African / African-American · 56/71,696 alleles

Filtering AF 0.0617% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0559%

Overall 0.00989% 151/1,526,144 alleles · ultra-rare exomes 112/1,373,848 · genomes 39/152,296 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0781%	1,280
Middle Eastern	0.0616%	1,623
Admixed American	0.0278%	3,595
Remaining individualsnot grpmax-eligible	0.0202%	4,960
South Asian	0.012%	8,320
East Asian	0.00758%	13,195
European (non-Finnish)	0.00455%	21,984
Finnishnot grpmax-eligible	0.00225%	44,486

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.Ala3Ser
Coding: c.7G>T
MANE Select: NM_133259
dbSNP: rs200686732
Type: single nucleotide variant
Location: chr2:43995941 (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.Ala3Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
LRPPRC p.Ala3Val Uncertain significance ★ ⚠ same residue
LRPPRC p.Ala3Pro Uncertain significance ★ ⚠ same residue
LRPPRC p.Ala3= 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

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-ala3ser (accessed [today's date]).

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