Is LIPE p.Asp446= (c.1338C>T) pathogenic?

LIPE p.Asp446= (c.1338C>T) is classified Likely benign in LIPE (ClinVar, Single submitter, 1 submitter; last evaluated 2018-05-02). Very rare (popmax 0.00483%, nfe).

How common is LIPE p.Asp446= (c.1338C>T) in the general population?

LIPE p.Asp446= (c.1338C>T) is very rare (popmax 0.00483%, nfe) (gnomAD).

LIPE p.Asp446=

c.1338C>T · rs370746342 · VCV742140

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00483%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.9
Overall
CADD	0.654	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00483% European (non-Finnish) · 57/1,179,986 alleles

Filtering AF 0.00377% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00345%

Overall 0.00397% 64/1,613,962 alleles · very rare exomes 61/1,461,796 · genomes 3/152,166 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00483%	20,701
Remaining individualsnot grpmax-eligible	0.0048%	20,825
South Asian	0.00329%	30,360
African / African-American	0.00133%	74,922

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.Asp446=
Coding: c.1338C>T
MANE Select: NM_005357
dbSNP: rs370746342
Type: single nucleotide variant
Location: chr19:42410388 (GRCh38)
Gene constraint: LOEUF 0.932 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.77 · 1 PDB

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-asp446 (accessed [today's date]).

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