Is LIPE p.Met577Ile (c.1731G>A) pathogenic?

LIPE p.Met577Ile (c.1731G>A) is classified Uncertain significance in LIPE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). AlphaMissense: ambiguous (0.511); Ultra-rare (popmax 0.0276%, nfe); Associated with Inborn genetic diseases.

What condition is associated with LIPE p.Met577Ile (c.1731G>A)?

LIPE p.Met577Ile (c.1731G>A) is associated with Inborn genetic diseases (ClinVar).

How common is LIPE p.Met577Ile (c.1731G>A) in the general population?

LIPE p.Met577Ile (c.1731G>A) is ultra-rare (popmax 0.0276%, nfe) (gnomAD).

What do computational predictors say about LIPE p.Met577Ile (c.1731G>A)?

AlphaMissense predicts ambiguous (score 0.511) — an in-silico prediction, not a clinical call.

LIPE p.Met577Ile

c.1731G>A · VCV4623688

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.511 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0276%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.511	ambiguous
REVEL	0.166	moderately benign-leaning
SaProt	LLR -6.21	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.8	phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 25 kb · p 0.019 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0276% European (non-Finnish) · 321/1,164,794 alleles

Filtering AF 0.0251% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0241%

Overall 0.0218% 344/1,580,356 alleles · ultra-rare exomes 325/1,428,244 · genomes 19/152,112 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0276%	3,629
Finnishnot grpmax-eligible	0.0207%	4,831
Remaining individualsnot grpmax-eligible	0.0115%	8,712
Ashkenazi Jewishnot grpmax-eligible	0.00371%	26,986
African / African-American	0.00271%	36,880

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.Met577Ile
Coding: c.1731G>A
MANE Select: NM_005357
Type: single nucleotide variant
Location: chr19:42407717 (GRCh38)
Gene constraint: LOEUF 0.932 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.77 · 1 PDB
Residue 577: a β-strand

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-met577ile (accessed [today's date]).

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