Is LPIN2 p.Ala172= (c.516C>T) pathogenic?

LPIN2 p.Ala172= (c.516C>T) is classified Conflicting classifications of pathogenicity in LPIN2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-02-13). Ultra-rare (popmax 0.0725%, sas); Associated with Majeed syndrome.

What condition is associated with LPIN2 p.Ala172= (c.516C>T)?

LPIN2 p.Ala172= (c.516C>T) is associated with Majeed syndrome, autoinflammatory syndrome (ClinVar).

How common is LPIN2 p.Ala172= (c.516C>T) in the general population?

LPIN2 p.Ala172= (c.516C>T) is ultra-rare (popmax 0.0725%, sas) (gnomAD).

How is Majeed syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

LPIN2 p.Ala172=

c.516C>T · rs150312425 · VCV514066

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0725%, sas)

Conditions

Majeed syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -4.7	GERP -3.5
Overall
CADD	0.453	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0725% South Asian · 66/91,068 alleles

Filtering AF 0.0584% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0533%

Overall 0.00985% 159/1,614,060 alleles · ultra-rare exomes 121/1,461,866 · genomes 38/152,194 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0725%	1,380
African / African-American	0.0707%	1,415
Ashkenazi Jewishnot grpmax-eligible	0.0405%	2,467
Remaining individualsnot grpmax-eligible	0.0096%	10,418
East Asian	0.00891%	11,221
Admixed American	0.005%	20,001
European (non-Finnish)	0.00127%	78,666

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: LPIN2
Protein: p.Ala172=
Coding: c.516C>T
MANE Select: NM_001375808
dbSNP: rs150312425
Type: single nucleotide variant
Location: chr18:2951129 (GRCh38)
Gene constraint: LOEUF 0.582 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 61.12
Residue 172: the 'disordered' region

Full LPIN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Majeed syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autoinflammatory syndrome

For Majeed syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

LPIN2 c.1269-2A>G Likely pathogenic ★★ same condition
LPIN2 c.698+1G>A Likely pathogenic ★★ same condition
LPIN2 c.699-2A>G Likely pathogenic ★★ same condition
LPIN2 p.Arg157Ter Pathogenic ★★ same condition
LPIN2 p.Arg197Ter Pathogenic/Likely pathogenic ★★ same condition
LPIN2 p.Arg280Ter Pathogenic/Likely pathogenic ★★ same condition
LPIN2 p.Arg517His Pathogenic/Likely pathogenic ★★ ⚠ same condition
LPIN2 p.Ser734Leu Pathogenic/Likely pathogenic ★★ 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/lpin2-p-ala172 (accessed [today's date]).

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