Is DXO p.Pro168Leu (c.503C>T) pathogenic?

DXO p.Pro168Leu (c.503C>T) is classified Uncertain significance in DXO (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: likely benign (0.0996); Very rare (popmax 0.000339%, nfe).

How common is DXO p.Pro168Leu (c.503C>T) in the general population?

DXO p.Pro168Leu (c.503C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about DXO p.Pro168Leu (c.503C>T)?

AlphaMissense predicts likely benign (score 0.0996) — an in-silico prediction, not a clinical call.

DXO p.Pro168Leu

c.503C>T · rs769891437 · VCV2543547

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0996 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0996	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -10.94	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP -2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 1,795 bp · p 0.43 · regional, not allelic
Overall
CADD	21.6	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 0.000339% European (non-Finnish) · 4/1,180,008 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,460,756 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: DXO
Protein: p.Pro168Leu
Coding: c.503C>T
MANE Select: NM_005510
dbSNP: rs769891437
Type: single nucleotide variant
Location: chr6:31971001 (GRCh38)
Gene constraint: LOEUF 1.264 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.96

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

Similar variants

DXO p.Ala338Thr Uncertain significance ★ ⚠ same type
DXO p.Ala372Thr Uncertain significance ★ ⚠ same type
DXO p.Ala64Asp Uncertain significance ★ ⚠ same type
DXO p.Arg145Gln Uncertain significance ★ ⚠ same type
DXO p.Arg155Gly Uncertain significance ★ ⚠ same type
DXO p.Arg177Gln Uncertain significance ★ ⚠ same type
DXO p.Arg177Trp Uncertain significance ★ ⚠ same type
DXO p.Arg221Cys 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/dxo-p-pro168leu (accessed [today's date]).

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