Is LIPE p.Pro139Ala (c.415C>G) pathogenic?

LIPE p.Pro139Ala (c.415C>G) is classified Uncertain significance in LIPE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-23). AlphaMissense: likely benign (0.0613); Ultra-rare (popmax 0.0254%, afr); Associated with Inborn genetic diseases.

What condition is associated with LIPE p.Pro139Ala (c.415C>G)?

LIPE p.Pro139Ala (c.415C>G) is associated with Inborn genetic diseases (ClinVar).

How common is LIPE p.Pro139Ala (c.415C>G) in the general population?

LIPE p.Pro139Ala (c.415C>G) is ultra-rare (popmax 0.0254%, afr) (gnomAD).

What do computational predictors say about LIPE p.Pro139Ala (c.415C>G)?

AlphaMissense predicts likely benign (score 0.0613) — an in-silico prediction, not a clinical call.

LIPE p.Pro139Ala

c.415C>G · rs145286581 · VCV2462582

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0613 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0254%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0613	likely benign
REVEL	0.013	strongly benign-leaning
SaProt	LLR -7.77	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 -12
Regional constraint	o/e 0.94	unconstrained · MANE · 25 kb · p 0.019 · regional, not allelic
Overall
CADD	0.07	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 0.0254% African / African-American · 19/74,908 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00149% 24/1,614,084 alleles · ultra-rare exomes 18/1,461,892 · genomes 6/152,192 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0254%	3,943
South Asian	0.00549%	18,218

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.Pro139Ala
Coding: c.415C>G
MANE Select: NM_005357
dbSNP: rs145286581
Type: single nucleotide variant
Location: chr19:42426735 (GRCh38)
Gene constraint: LOEUF 0.932 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.77 · 1 PDB
Residue 139: the 'disordered' region

Full LIPE 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

LIPE p.Gln150Glu Uncertain significance ★★ ⚠ same condition
LIPE p.Leu777Phe Uncertain significance ★★ ⚠ same condition
LIPE p.Asn499= Likely benign ★★ same condition
LIPE p.Gly445= Likely benign ★★ same condition
LIPE p.Ala1055Ser Uncertain significance ★ ⚠ same condition
LIPE p.Ala159Thr Uncertain significance ★ ⚠ same condition
LIPE p.Ala345Val Uncertain significance ★ ⚠ same condition
LIPE p.Ala351Val 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-pro139ala (accessed [today's date]).

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