Is LIPE p.Arg423= (c.1269C>T) pathogenic?

LIPE p.Arg423= (c.1269C>T) is classified Benign in LIPE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-06-09). Common (popmax 10.2%, afr) — too common for a highly-penetrant pathogenic allele.

LIPE p.Arg423=

Q: How common is LIPE p.Arg423= (c.1269C>T) in the general population?

LIPE p.Arg423= (c.1269C>T) is common (popmax 10.2%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1269C>T · rs34044249 · VCV1295104

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 10.2%, afr) — too common for a highly-penetrant pathogenic allele

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 -14
Overall
CADD	1.72	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 10.2% African / African-American · 7,669/75,040 alleles

Filtering AF 10% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.95%

Overall 0.587% 9,480/1,614,088 alleles · common exomes 4,957/1,461,760 · genomes 4,523/152,328 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	10.2%	10
Admixed American	0.956%	105
Remaining individualsnot grpmax-eligible	0.782%	128
Middle Eastern	0.61%	164
Ashkenazi Jewishnot grpmax-eligible	0.338%	296
European (non-Finnish)	0.0505%	1,980
South Asian	0.0154%	6,506
Finnishnot grpmax-eligible	0.00156%	63,934

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.Arg423=
Coding: c.1269C>T
MANE Select: NM_005357
dbSNP: rs34044249
Type: single nucleotide variant
Location: chr19:42410457 (GRCh38)
Gene constraint: LOEUF 0.932 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.77 · 1 PDB
Residue 423: an α-helix

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-arg423 (accessed [today's date]).

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