Is OSBPL2 p.Pro126Ser (c.376C>T) pathogenic?

OSBPL2 p.Pro126Ser (c.376C>T) is classified Uncertain significance in OSBPL2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-10). AlphaMissense: likely benign (0.0822); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with OSBPL2 p.Pro126Ser (c.376C>T)?

OSBPL2 p.Pro126Ser (c.376C>T) is associated with Inborn genetic diseases (ClinVar).

How common is OSBPL2 p.Pro126Ser (c.376C>T) in the general population?

OSBPL2 p.Pro126Ser (c.376C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about OSBPL2 p.Pro126Ser (c.376C>T)?

AlphaMissense predicts likely benign (score 0.0822) — an in-silico prediction, not a clinical call.

OSBPL2 p.Pro126Ser

c.376C>T · VCV3303552

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0822 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0822	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -6.40	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 0.68	GERP -4.7, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 1,090 bp · p 0.48 · regional, not allelic
Overall
CADD	12.27	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,970 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000744% 12/1,613,318 alleles · very rare exomes 11/1,461,304 · genomes 1/152,014 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,985
European (non-Finnish)	0.000848%	117,986

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: OSBPL2
Protein: p.Pro126Ser
Coding: c.376C>T
MANE Select: NM_144498
Type: single nucleotide variant
Location: chr20:62272242 (GRCh38)
Gene constraint: LOEUF 0.467 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 83.92 · 1 PDB
Residue 126: an α-helix

Full OSBPL2 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

OSBPL2 p.Arg434Trp Uncertain significance ★★ same condition
OSBPL2 p.Asp475Asn Uncertain significance ★★ ⚠ same condition
OSBPL2 p.Gln58Pro Uncertain significance ★★ ⚠ same condition
OSBPL2 p.Glu284Gly Uncertain significance ★★ same condition
OSBPL2 p.Gly245Arg Uncertain significance ★★ ⚠ same condition
OSBPL2 p.Ile34Val Uncertain significance ★★ ⚠ same condition
OSBPL2 p.Ile479Thr Uncertain significance ★★ ⚠ same condition
OSBPL2 p.Lys203Gln 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/osbpl2-p-pro126ser (accessed [today's date]).

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