Is LPIN2 p.Pro623Ser (c.1867C>T) pathogenic?

LPIN2 p.Pro623Ser (c.1867C>T) is classified Benign/Likely benign in LPIN2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-03-31). AlphaMissense: likely benign (0.0742); Low-frequency (popmax 2.88%, afr); Associated with autoinflammatory syndrome.

What condition is associated with LPIN2 p.Pro623Ser (c.1867C>T)?

LPIN2 p.Pro623Ser (c.1867C>T) is associated with autoinflammatory syndrome, Majeed syndrome (ClinVar).

How common is LPIN2 p.Pro623Ser (c.1867C>T) in the general population?

LPIN2 p.Pro623Ser (c.1867C>T) is low-frequency (popmax 2.88%, afr) (gnomAD).

What do computational predictors say about LPIN2 p.Pro623Ser (c.1867C>T)?

AlphaMissense predicts likely benign (score 0.0742) — an in-silico prediction, not a clinical call.

LPIN2 p.Pro623Ser

c.1867C>T · rs143090653 · VCV245641

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0742 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.88%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
AlphaMissense	0.0742	likely benign
REVEL	0.146	moderately benign-leaning
SaProt	LLR -6.48	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 1.6	GERP -0.085, phastCons 0.91
Regional constraint	o/e 0.94	unconstrained · MANE · 31 kb · p 0.11 · regional, not allelic
Overall
CADD	9.831	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 2.88% African / African-American · 2,162/75,034 alleles

Filtering AF 2.78% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.74%

Overall 0.158% 2,557/1,614,160 alleles · low-frequency exomes 1,322/1,461,872 · genomes 1,235/152,288 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.88%	35
Middle Eastern	0.412%	242
Remaining individualsnot grpmax-eligible	0.219%	456
Admixed American	0.16%	625
European (non-Finnish)	0.0106%	9,440
Finnishnot grpmax-eligible	0.00781%	12,808
South Asian	0.00769%	13,012

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.Pro623Ser
Coding: c.1867C>T
MANE Select: NM_001375808
dbSNP: rs143090653
Type: single nucleotide variant
Location: chr18:2925295 (GRCh38)
Gene constraint: LOEUF 0.582 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 61.12
Residue 623: the 'disordered' region

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

Disease context

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

Also linked: Majeed syndrome

Similar variants

LPIN2 p.Pro623Leu Uncertain significance ★ ⚠ same residue
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

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-pro623ser (accessed [today's date]).

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