Is LIPE p.Ala686Val (c.2057C>T) pathogenic?

LIPE p.Ala686Val (c.2057C>T) is classified Uncertain significance in LIPE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-05). AlphaMissense: likely pathogenic (0.895); Very rare (popmax 0.000512%, nfe); Associated with Inborn genetic diseases.

What condition is associated with LIPE p.Ala686Val (c.2057C>T)?

LIPE p.Ala686Val (c.2057C>T) is associated with Inborn genetic diseases (ClinVar).

How common is LIPE p.Ala686Val (c.2057C>T) in the general population?

LIPE p.Ala686Val (c.2057C>T) is very rare (popmax 0.000512%, nfe) (gnomAD).

What do computational predictors say about LIPE p.Ala686Val (c.2057C>T)?

AlphaMissense predicts likely pathogenic (score 0.895) — an in-silico prediction, not a clinical call.

LIPE p.Ala686Val

c.2057C>T · VCV4098238

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.895 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000512%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.895	likely pathogenic
REVEL	0.412	indeterminate
SaProt	LLR -13.42	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 25 kb · p 0.019 · regional, not allelic
Overall
CADD	28.5	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 0.000512% European (non-Finnish) · 6/1,172,640 alleles

Filtering AF 0.000184% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000415% 6/1,445,948 alleles · very rare

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.Ala686Val
Coding: c.2057C>T
MANE Select: NM_005357
Type: single nucleotide variant
Location: chr19:42407254 (GRCh38)
Gene constraint: LOEUF 0.932 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.77 · 1 PDB
Residue 686: a turn

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-ala686val (accessed [today's date]).

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