Is XPR1 p.Ser136= (c.408T>C) pathogenic?

XPR1 p.Ser136= (c.408T>C) is classified Benign in XPR1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-02). Common (popmax 14.8%, afr) — too common for a highly-penetrant pathogenic allele.

XPR1 p.Ser136=

Q: How common is XPR1 p.Ser136= (c.408T>C) in the general population?

XPR1 p.Ser136= (c.408T>C) is common (popmax 14.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.408T>C · rs12078050 · VCV1287169

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 14.8%, afr) — too common for a highly-penetrant pathogenic allele

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 -1.9	GERP -2.9
Overall
CADD	6.427	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 14.8% African / African-American · 11,085/74,970 alleles

Filtering AF 14.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 14.5%

Overall 0.804% 12,975/1,613,122 alleles · common exomes 6,430/1,460,848 · genomes 6,545/152,274 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	14.8%	7
Admixed American	1.23%	81
Remaining individualsnot grpmax-eligible	1.17%	85
Middle Eastern	0.7%	143
South Asian	0.0373%	2,678
European (non-Finnish)	0.0289%	3,460
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,866
East Asian	0.00223%	44,886

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.Ser136=
Coding: c.408T>C
MANE Select: NM_004736
dbSNP: rs12078050
Type: single nucleotide variant
Location: chr1:180803572 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.31 · 51 PDB
Residue 136: the spx domain; a UniProt-annotated variant site (in ibgc6; phosphate efflux is impaired; present at the plasma membrane); an α-helix

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

Similar variants

XPR1 p.Ser136Asn Pathogenic ⚠ same residue
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

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-ser136 (accessed [today's date]).

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