Is LIPE p.Pro21= (c.63T>C) pathogenic?

LIPE p.Pro21= (c.63T>C) is classified Likely benign in LIPE (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-08-22). Very rare (popmax 0.00119%, nfe); Associated with LIPE-related disorder.

What condition is associated with LIPE p.Pro21= (c.63T>C)?

LIPE p.Pro21= (c.63T>C) is associated with LIPE-related disorder (ClinVar).

How common is LIPE p.Pro21= (c.63T>C) in the general population?

LIPE p.Pro21= (c.63T>C) is very rare (popmax 0.00119%, nfe) (gnomAD).

LIPE p.Pro21=

c.63T>C · VCV3357216

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Conditions

LIPE-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.56
Overall
CADD	0.555	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00119% European (non-Finnish) · 14/1,179,964 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000867% 14/1,613,900 alleles · very rare exomes 14/1,461,674 · genomes 0/152,226 · 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: LIPE
Protein: p.Pro21=
Coding: c.63T>C
MANE Select: NM_005357
Type: single nucleotide variant
Location: chr19:42427087 (GRCh38)
Gene constraint: LOEUF 0.932 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.77 · 1 PDB
Residue 21: the 'disordered' region

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

Disease context

LIPE-related disorder

Similar variants

LIPE p.Arg821Cys Uncertain significance ★★ ⚠ same condition
LIPE p.Glu688Ter Likely pathogenic ★ same condition
LIPE c.-32G>C Uncertain significance ★ same condition
LIPE p.Asp582Asn Uncertain significance ⚠ same condition
LIPE c.2968-9G>C Likely benign same condition
LIPE p.Ala1030= Likely benign same condition
LIPE p.Glu833= Likely benign same condition
LIPE p.Leu913fs 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/lipe-p-pro21 (accessed [today's date]).

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