Is XPR1 p.Val451= (c.1353T>C) pathogenic?

XPR1 p.Val451= (c.1353T>C) is classified Likely benign in XPR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-01). Very rare (popmax 0.00153%, nfe).

How common is XPR1 p.Val451= (c.1353T>C) in the general population?

XPR1 p.Val451= (c.1353T>C) is very rare (popmax 0.00153%, nfe) (gnomAD).

XPR1 p.Val451=

c.1353T>C · VCV3633847

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.2	GERP -1.4, phastCons 1
Overall
CADD	8.554	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00153% European (non-Finnish) · 18/1,180,056 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00124% 20/1,614,098 alleles · very rare exomes 19/1,461,888 · genomes 1/152,210 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)grpmax	0.00153%	65,559
South Asian	0.0011%	91,086

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val451=
Coding: c.1353T>C
MANE Select: NM_004736
Type: single nucleotide variant
Location: chr1:180836568 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.31 · 51 PDB
Residue 451: an α-helix; the exs domain

Full XPR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

XPR1 p.Ala254= Uncertain significance ★★ same type
XPR1 p.Ala572Val Uncertain significance ★★ ⚠ same type
XPR1 p.Arg110Cys Uncertain significance ★★ ⚠ same type
XPR1 p.Arg176Ter Uncertain significance ★★ same type
XPR1 p.Arg604Gln Uncertain significance ★★ ⚠ same type
XPR1 p.Arg653Gln Uncertain significance ★★ ⚠ same type
XPR1 p.Arg655Gly Uncertain significance ★★ ⚠ same type
XPR1 p.Arg659Gln 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/xpr1-p-val451 (accessed [today's date]).

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