Is LEO1 p.Ser84Pro (c.250T>C) pathogenic?

LEO1 p.Ser84Pro (c.250T>C) is classified Uncertain significance in LEO1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-09). AlphaMissense: likely benign (0.1397); Very rare (popmax 0.00934%, afr).

How common is LEO1 p.Ser84Pro (c.250T>C) in the general population?

LEO1 p.Ser84Pro (c.250T>C) is very rare (popmax 0.00934%, afr) (gnomAD).

What do computational predictors say about LEO1 p.Ser84Pro (c.250T>C)?

AlphaMissense predicts likely benign (score 0.1397) — an in-silico prediction, not a clinical call.

LEO1 p.Ser84Pro

c.250T>C · VCV3866898

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1397 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00934%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1397	likely benign
REVEL	0.338	indeterminate
SaProt	LLR -11.57	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.1	GERP 1.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 11 kb · p 0.94 · regional, not allelic
Overall
CADD	26.1	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 0.00934% African / African-American · 7/74,908 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000496% 8/1,613,978 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00934%	10,701
European (non-Finnish)	8.47e-05%	1,180,030

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: LEO1
Protein: p.Ser84Pro
Coding: c.250T>C
MANE Select: NM_138792
Type: single nucleotide variant
Location: chr15:51966313 (GRCh38)
Gene constraint: LOEUF 0.488 · pLI 0.99 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 54.94 · 20 PDB
Residue 84: the 'disordered' region

Full LEO1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

LEO1 p.Ser84Leu Uncertain significance ★ ⚠ same residue
LEO1 p.Ser507Pro Uncertain significance ★★ ⚠ same type
LEO1 p.Gln203Ter Likely pathogenic ★ same type
LEO1 p.Leu471Ile Likely pathogenic ★ same type
LEO1 p.Pro493Arg Likely pathogenic ★ same type
LEO1 c.1246-11T>G Uncertain significance ★ same type
LEO1 p.Ala12Ser Uncertain significance ★ ⚠ same type
LEO1 p.Ala132Thr Uncertain significance ★ ⚠ 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/leo1-p-ser84pro (accessed [today's date]).

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