Is XPR1 p.Ser668Pro (c.2002T>C) pathogenic?

XPR1 p.Ser668Pro (c.2002T>C) is classified Uncertain significance in XPR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: likely benign (0.0905); Very rare (popmax 0.00891%, eas); Associated with Inborn genetic diseases.

What condition is associated with XPR1 p.Ser668Pro (c.2002T>C)?

XPR1 p.Ser668Pro (c.2002T>C) is associated with Inborn genetic diseases (ClinVar).

How common is XPR1 p.Ser668Pro (c.2002T>C) in the general population?

XPR1 p.Ser668Pro (c.2002T>C) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about XPR1 p.Ser668Pro (c.2002T>C)?

AlphaMissense predicts likely benign (score 0.0905) — an in-silico prediction, not a clinical call.

XPR1 p.Ser668Pro

c.2002T>C · VCV4202839

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0905 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0905	likely benign
REVEL	0.117	moderately benign-leaning
SaProt	LLR -7.70	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 0.73	GERP 1.2, phastCons 0.94
Regional constraint	o/e 0.80	unconstrained · MANE · 3,921 bp · p 0.05 · regional, not allelic
Overall
CADD	21.4	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 0.00891% East Asian · 4/44,878 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000248% 4/1,614,148 alleles · very rare exomes 4/1,461,894 · genomes 0/152,254 · joint denominator

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: XPR1
Protein: p.Ser668Pro
Coding: c.2002T>C
MANE Select: NM_004736
Type: single nucleotide variant
Location: chr1:180880269 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.31 · 51 PDB
Residue 668: a modified residue (phosphoserine)

Full XPR1 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

XPR1 p.Ser668Cys Uncertain significance ★ ⚠ same residue
XPR1 p.Ala572Val Uncertain significance ★★ ⚠ same condition
XPR1 p.Arg110Cys Uncertain significance ★★ ⚠ same condition
XPR1 p.Arg655Gly Uncertain significance ★★ ⚠ same condition
XPR1 p.Arg659Gln Uncertain significance ★★ ⚠ same condition
XPR1 p.Arg670His Uncertain significance ★★ ⚠ same condition
XPR1 p.Arg671Gln Uncertain significance ★★ ⚠ same condition
XPR1 p.Arg681Cys 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/xpr1-p-ser668pro (accessed [today's date]).

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