Is XRN2 p.Pro449Ser (c.1345C>T) pathogenic?

XRN2 p.Pro449Ser (c.1345C>T) is classified Uncertain significance in XRN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-23). AlphaMissense: likely benign (0.0558); Ultra-rare (popmax 0.099%, mid).

How common is XRN2 p.Pro449Ser (c.1345C>T) in the general population?

XRN2 p.Pro449Ser (c.1345C>T) is ultra-rare (popmax 0.099%, mid) (gnomAD).

What do computational predictors say about XRN2 p.Pro449Ser (c.1345C>T)?

AlphaMissense predicts likely benign (score 0.0558) — an in-silico prediction, not a clinical call.

XRN2 p.Pro449Ser

c.1345C>T · rs201052387 · VCV2340190

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0558 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.099%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0558	likely benign
REVEL	0.124	moderately benign-leaning
SaProt	LLR -5.93	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 2.5	GERP 2, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 20 kb · p 4.8e-06 · regional, not allelic
Overall
CADD	19.23	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 0.099% Middle Eastern · 6/6,058 alleles

Filtering AF 0.043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0295%

Overall 0.00589% 95/1,613,952 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.099%	1,010
Admixed American	0.03%	3,334
Remaining individualsnot grpmax-eligible	0.0208%	4,808
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,865
South Asian	0.00549%	18,215
European (non-Finnish)	0.00415%	24,080
African / African-American	0.00133%	75,002

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: XRN2
Protein: p.Pro449Ser
Coding: c.1345C>T
MANE Select: NM_012255
dbSNP: rs201052387
Type: single nucleotide variant
Location: chr20:21340787 (GRCh38)
Gene constraint: LOEUF 0.413 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.15
Residue 449: the 'disordered' region

Full XRN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

XRN2 p.Ala297Val Uncertain significance ★ ⚠ same type
XRN2 p.Ala442Pro Uncertain significance ★ ⚠ same type
XRN2 p.Ala648Pro Uncertain significance ★ ⚠ same type
XRN2 p.Ala648Ser Uncertain significance ★ same type
XRN2 p.Ala834Gly Uncertain significance ★ ⚠ same type
XRN2 p.Ala887Gly Uncertain significance ★ ⚠ same type
XRN2 p.Arg134Gln Uncertain significance ★ ⚠ same type
XRN2 p.Arg175Cys 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/xrn2-p-pro449ser (accessed [today's date]).

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