Is ADO p.Pro83Leu (c.248C>T) pathogenic?

ADO p.Pro83Leu (c.248C>T) is classified Uncertain significance in ADO (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-14). AlphaMissense: likely pathogenic (0.9278); Very rare (popmax 0.000594%, nfe).

How common is ADO p.Pro83Leu (c.248C>T) in the general population?

ADO p.Pro83Leu (c.248C>T) is very rare (popmax 0.000594%, nfe) (gnomAD).

What do computational predictors say about ADO p.Pro83Leu (c.248C>T)?

AlphaMissense predicts likely pathogenic (score 0.9278) — an in-silico prediction, not a clinical call.

ADO p.Pro83Leu

c.248C>T · VCV3501717

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9278 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000594%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9278	likely pathogenic
REVEL	0.252	benign-leaning
SaProt	LLR -12.76	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 809 bp · p 0.12 · regional, not allelic
Overall
CADD	26.2	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 0.000594% European (non-Finnish) · 7/1,179,296 alleles

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

Overall 0.000482% 7/1,451,850 alleles · very rare

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: ADO
Protein: p.Pro83Leu
Coding: c.248C>T
MANE Select: NM_032804
Type: single nucleotide variant
Location: chr10:62805307 (GRCh38)
Gene constraint: LOEUF 1.476 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.28 · 9 PDB

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

Similar variants

ADO p.Ala146Val Uncertain significance ★ ⚠ same type
ADO p.Ala14Ser Uncertain significance ★ ⚠ same type
ADO p.Ala41Val Uncertain significance ★ ⚠ same type
ADO p.Arg230Gly Uncertain significance ★ ⚠ same type
ADO p.Arg33Cys Uncertain significance ★ ⚠ same type
ADO p.Asp215Val Uncertain significance ★ ⚠ same type
ADO p.Asp219Glu Uncertain significance ★ ⚠ same type
ADO p.Asp34His 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/ado-p-pro83leu (accessed [today's date]).

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