Is LIPE p.Pro146Ser (c.436C>T) pathogenic?

LIPE p.Pro146Ser (c.436C>T) is classified Benign in LIPE (ClinVar, Single submitter, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0732); Low-frequency (popmax 2.64%, afr).

How common is LIPE p.Pro146Ser (c.436C>T) in the general population?

LIPE p.Pro146Ser (c.436C>T) is low-frequency (popmax 2.64%, afr) (gnomAD).

What do computational predictors say about LIPE p.Pro146Ser (c.436C>T)?

AlphaMissense predicts likely benign (score 0.0732) — an in-silico prediction, not a clinical call.

LIPE p.Pro146Ser

c.436C>T · rs34348028 · VCV716480

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0732 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.64%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0732	likely benign
REVEL	0.106	moderately benign-leaning
SaProt	LLR -5.27	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 0.82	phastCons 0.004
Regional constraint	o/e 0.94	unconstrained · MANE · 25 kb · p 0.019 · regional, not allelic
Overall
CADD	3.561	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 2.64% African / African-American · 1,981/75,044 alleles

Filtering AF 2.54% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5%

Overall 0.138% 2,233/1,614,170 alleles · low-frequency exomes 1,038/1,461,888 · genomes 1,195/152,282 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.64%	38
Admixed American	0.188%	531
Remaining individualsnot grpmax-eligible	0.166%	601
Middle Eastern	0.0495%	2,020
European (non-Finnish)	0.00271%	36,876

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.Pro146Ser
Coding: c.436C>T
MANE Select: NM_005357
dbSNP: rs34348028
Type: single nucleotide variant
Location: chr19:42426714 (GRCh38)
Gene constraint: LOEUF 0.932 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.77 · 1 PDB
Residue 146: the 'disordered' region; a UniProt-annotated variant site (in a breast cancer sample; somatic mutation); a UniProt-annotated variant site (in)

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

Similar variants

LIPE p.Arg305Cys Uncertain significance ★★ ⚠ same type
LIPE p.Arg821Cys Uncertain significance ★★ ⚠ same type
LIPE p.Gln150Glu Uncertain significance ★★ ⚠ same type
LIPE p.Leu1027Met Uncertain significance ★★ ⚠ same type
LIPE p.Leu777Phe Uncertain significance ★★ ⚠ same type
LIPE p.Val1014Met Uncertain significance ★★ ⚠ same type
LIPE c.2365+181T>A Benign ★★ same type
LIPE c.2968-44C>G Benign ★★ same type

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-pro146ser (accessed [today's date]).

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