Is LIPH p.Lys372= (c.1116A>G) pathogenic?

LIPH p.Lys372= (c.1116A>G) is classified Benign in LIPH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). Common (popmax 44.3%, nfe) — too common for a highly-penetrant pathogenic allele.

LIPH p.Lys372=

Q: How common is LIPH p.Lys372= (c.1116A>G) in the general population?

LIPH p.Lys372= (c.1116A>G) is common (popmax 44.3%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1116A>G · rs61730237 · VCV1228610

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 44.3%, nfe) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.20	acceptor gain, 21 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.22	GERP -2.1, phastCons 0.99
Overall
CADD	6.464	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 44.3% European (non-Finnish) · 520,385/1,175,664 alleles

Filtering AF 44.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 44.1%

Overall 42.1% 677,144/1,609,114 alleles · common exomes 615,654/1,457,228 · genomes 61,490/151,886 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	56.4%	2
European (non-Finnish)grpmax	44.3%	2
Ashkenazi Jewishnot grpmax-eligible	43.4%	2
Middle Eastern	41.7%	2
Remaining individualsnot grpmax-eligible	41%	2
Finnishnot grpmax-eligible	40.9%	2
Admixed American	38%	3
African / African-American	35.7%	3
East Asian	30.5%	3
South Asian	28.5%	4

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Lys372=
Coding: c.1116A>G
MANE Select: NM_139248
dbSNP: rs61730237
Type: single nucleotide variant
Location: chr3:185511676 (GRCh38)
Gene constraint: LOEUF 0.811 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.89
Residue 372: a UniProt-annotated variant site (in arwh2)

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

Similar variants

LIPH p.Arg110Ter Pathogenic/Likely pathogenic ★★ same type
LIPH p.Cys246Ser Pathogenic/Likely pathogenic ★★ same type
LIPH p.His248Asn Pathogenic/Likely pathogenic ★★ same type
LIPH p.Ala180Gly Uncertain significance ★★ ⚠ same type
LIPH p.Arg110Leu Uncertain significance ★★ ⚠ same type
LIPH p.Ile336Met Uncertain significance ★★ ⚠ same type
LIPH p.Thr286Met Uncertain significance ★★ ⚠ same type
LIPH c.1094+29C>T 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/liph-p-lys372 (accessed [today's date]).

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