Is LPIN1 p.Pro331Ser (c.991C>T) pathogenic?

LPIN1 p.Pro331Ser (c.991C>T) is classified Uncertain significance in LPIN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: likely benign (0.0682); Very rare (popmax 0.000593%, nfe); Associated with Inborn genetic diseases.

What condition is associated with LPIN1 p.Pro331Ser (c.991C>T)?

LPIN1 p.Pro331Ser (c.991C>T) is associated with Inborn genetic diseases (ClinVar).

How common is LPIN1 p.Pro331Ser (c.991C>T) in the general population?

LPIN1 p.Pro331Ser (c.991C>T) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about LPIN1 p.Pro331Ser (c.991C>T)?

AlphaMissense predicts likely benign (score 0.0682) — an in-silico prediction, not a clinical call.

LPIN1 p.Pro331Ser

c.991C>T · VCV4623799

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0682 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0682	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	LLR -6.45	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 3.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 59 kb · p 0.00055 · regional, not allelic
Overall
CADD	19.03	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P295S vs ClinVar P331S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000593% European (non-Finnish) · 7/1,179,992 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000496% 8/1,614,086 alleles · very rare exomes 8/1,461,836 · genomes 0/152,250 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)grpmax	0.000593%	168,570

Remaining individuals 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: LPIN1
Protein: p.Pro331Ser
Coding: c.991C>T
MANE Select: NM_001349206
Type: single nucleotide variant
Location: chr2:11782234 (GRCh38)
Gene constraint: LOEUF 0.784 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.88
Residue 295 UniProt numbering: the 'disordered' region

Full LPIN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LPIN1 p.Ala391Val Uncertain significance ★★ ⚠ same condition
LPIN1 p.Ala430Val Uncertain significance ★★ ⚠ same condition
LPIN1 p.Ala460Val Uncertain significance ★★ ⚠ same condition
LPIN1 p.Arg37Pro Uncertain significance ★★ ⚠ same condition
LPIN1 p.Arg61Gln Uncertain significance ★★ ⚠ same condition
LPIN1 p.Arg696Cys Uncertain significance ★★ ⚠ same condition
LPIN1 p.Arg696His Uncertain significance ★★ ⚠ same condition
LPIN1 p.Arg837Gln Uncertain significance ★★ ⚠ 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/lpin1-p-pro331ser (accessed [today's date]).

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