Is LONP1 p.Phe504Leu (c.1510T>C) pathogenic?

LONP1 p.Phe504Leu (c.1510T>C) is classified Uncertain significance in LONP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-30). AlphaMissense: likely pathogenic (0.9937); Very rare (popmax 0.00272%, sas); Associated with Inborn genetic diseases.

What condition is associated with LONP1 p.Phe504Leu (c.1510T>C)?

LONP1 p.Phe504Leu (c.1510T>C) is associated with Inborn genetic diseases (ClinVar).

How common is LONP1 p.Phe504Leu (c.1510T>C) in the general population?

LONP1 p.Phe504Leu (c.1510T>C) is very rare (popmax 0.00272%, sas) (gnomAD).

What do computational predictors say about LONP1 p.Phe504Leu (c.1510T>C)?

AlphaMissense predicts likely pathogenic (score 0.9937) — an in-silico prediction, not a clinical call.

LONP1 p.Phe504Leu

c.1510T>C · rs575991610 · VCV2614765

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9937 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00272%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9937	likely pathogenic
REVEL	0.583	indeterminate
SaProt	LLR -12.91	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 6,951 bp · p 0.16 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00272% South Asian · 2/73,568 alleles

Filtering AF 0.000451% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000169%

Overall 0.000135% 2/1,486,972 alleles · very rare exomes 1/1,334,754 · genomes 1/152,218 · 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: LONP1
Protein: p.Phe504Leu
Coding: c.1510T>C
MANE Select: NM_004793
dbSNP: rs575991610
Type: single nucleotide variant
Location: chr19:5699202 (GRCh38)
Gene constraint: LOEUF 0.448 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.35 · 36 PDB
Residue 504: an α-helix

Full LONP1 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

LONP1 p.Ala27Ser Uncertain significance ★★ ⚠ same condition
LONP1 p.Ala337Thr Uncertain significance ★★ ⚠ same condition
LONP1 p.Ala901Val Uncertain significance ★★ ⚠ same condition
LONP1 p.Arg422Trp Uncertain significance ★★ ⚠ same condition
LONP1 p.Arg424Cys Uncertain significance ★★ ⚠ same condition
LONP1 p.Arg546His Uncertain significance ★★ ⚠ same condition
LONP1 p.Arg679Cys Uncertain significance ★★ ⚠ same condition
LONP1 p.Asn354Ser 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/lonp1-p-phe504leu (accessed [today's date]).

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