Is LRPPRC p.Phe74Leu (c.222T>G) pathogenic?

LRPPRC p.Phe74Leu (c.222T>G) is classified Uncertain significance in LRPPRC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-14). AlphaMissense: likely benign (0.2974); Ultra-rare (popmax 0.025%, amr); Associated with Inborn genetic diseases.

What condition is associated with LRPPRC p.Phe74Leu (c.222T>G)?

LRPPRC p.Phe74Leu (c.222T>G) is associated with Inborn genetic diseases (ClinVar).

How common is LRPPRC p.Phe74Leu (c.222T>G) in the general population?

LRPPRC p.Phe74Leu (c.222T>G) is ultra-rare (popmax 0.025%, amr) (gnomAD).

What do computational predictors say about LRPPRC p.Phe74Leu (c.222T>G)?

AlphaMissense predicts likely benign (score 0.2974) — an in-silico prediction, not a clinical call.

LRPPRC p.Phe74Leu

c.222T>G · rs554391739 · VCV2081150

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2974 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.025%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2974	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -5.40	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 0.59	GERP -2.2
Regional constraint	o/e 1.21	unconstrained · MANE · 107 kb · p 2.9e-18 · regional, not allelic
Overall
CADD	3.207	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.025% Admixed American · 15/60,022 alleles

Filtering AF 0.0153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.00142% 23/1,614,078 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.025%	4,001
Remaining individualsnot grpmax-eligible	0.008%	12,501
African / African-American	0.004%	25,019

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.Phe74Leu
Coding: c.222T>G
MANE Select: NM_133259
dbSNP: rs554391739
Type: single nucleotide variant
Location: chr2:43982362 (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 74: an α-helix

Full LRPPRC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LRPPRC c.1369+5G>A Uncertain significance ★★ same condition
LRPPRC p.Ala1093Thr Uncertain significance ★★ ⚠ same condition
LRPPRC p.Ala1360Ser Uncertain significance ★★ ⚠ same condition
LRPPRC p.Ala37Ser Uncertain significance ★★ ⚠ same condition
LRPPRC p.Ala417Thr Uncertain significance ★★ ⚠ same condition
LRPPRC p.Ala516Val Uncertain significance ★★ ⚠ same condition
LRPPRC p.Ala997Thr Uncertain significance ★★ ⚠ same condition
LRPPRC p.Arg1109Cys Uncertain significance ★★ ⚠ 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-phe74leu (accessed [today's date]).

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