Is LIPH p.Leu45Pro (c.134T>C) pathogenic?

LIPH p.Leu45Pro (c.134T>C) is classified Uncertain significance in LIPH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-28). AlphaMissense: likely pathogenic (0.9634); Ultra-rare (popmax 0.0417%, sas); Associated with Inborn genetic diseases.

What condition is associated with LIPH p.Leu45Pro (c.134T>C)?

LIPH p.Leu45Pro (c.134T>C) is associated with Inborn genetic diseases (ClinVar).

How common is LIPH p.Leu45Pro (c.134T>C) in the general population?

LIPH p.Leu45Pro (c.134T>C) is ultra-rare (popmax 0.0417%, sas) (gnomAD).

What do computational predictors say about LIPH p.Leu45Pro (c.134T>C)?

AlphaMissense predicts likely pathogenic (score 0.9634) — an in-silico prediction, not a clinical call.

LIPH p.Leu45Pro

c.134T>C · VCV3538490

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9634 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0417%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9634	likely pathogenic · top 4% in LIPH
REVEL	0.949	strongly pathogenic-leaning
SaProt	LLR -16.60	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 44 kb · p 0.056 · regional, not allelic
Overall
CADD	24.7	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 0.0417% South Asian · 38/91,058 alleles

Filtering AF 0.0312% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0276%

Overall 0.00279% 45/1,613,744 alleles · ultra-rare exomes 42/1,461,612 · genomes 3/152,132 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0417%	2,396
Middle Eastern	0.0329%	3,042
Remaining individualsnot grpmax-eligible	0.0048%	20,826
European (non-Finnish)	0.00017%	589,943

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: LIPH
Protein: p.Leu45Pro
Coding: c.134T>C
MANE Select: NM_139248
Type: single nucleotide variant
Location: chr3:185535048 (GRCh38)
Gene constraint: LOEUF 0.811 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.89

Full LIPH 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

LIPH p.Ala180Gly Uncertain significance ★★ ⚠ same condition
LIPH p.Arg110Leu Uncertain significance ★★ ⚠ same condition
LIPH p.Ile336Met Uncertain significance ★★ ⚠ same condition
LIPH p.Ala180Thr Uncertain significance ★ ⚠ same condition
LIPH p.Ala198Val Uncertain significance ★ ⚠ same condition
LIPH p.Ala267Glu Uncertain significance ★ ⚠ same condition
LIPH p.Ala54Thr Uncertain significance ★ ⚠ same condition
LIPH p.Arg110Gln 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/liph-p-leu45pro (accessed [today's date]).

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