Is XRCC2 p.Pro49= (c.147A>G) pathogenic?

XRCC2 p.Pro49= (c.147A>G) is classified Likely benign in XRCC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-01). Ultra-rare (popmax 0.0193%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with XRCC2 p.Pro49= (c.147A>G)?

XRCC2 p.Pro49= (c.147A>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is XRCC2 p.Pro49= (c.147A>G) in the general population?

XRCC2 p.Pro49= (c.147A>G) is ultra-rare (popmax 0.0193%, sas) (gnomAD).

XRCC2 p.Pro49=

c.147A>G · rs770063304 · VCV1528320

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0193%, sas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.63	GERP 1.9, phastCons 0.058
Overall
CADD	8.673	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0193% South Asian · 17/87,982 alleles

Filtering AF 0.0122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.00113% 18/1,594,716 alleles · ultra-rare exomes 18/1,442,396 · genomes 0/152,320 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0193%	5,175
Remaining individualsnot grpmax-eligible	0.00162%	61,650

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: XRCC2
Protein: p.Pro49=
Coding: c.147A>G
MANE Select: NM_005431
dbSNP: rs770063304
Type: single nucleotide variant
Location: chr7:152649338 (GRCh38)
Gene constraint: LOEUF 1.209 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.57 · 16 PDB

Full XRCC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

XRCC2 p.Pro49Leu Uncertain significance ★ ⚠ same residue
XRCC2 c.39+5G>C Uncertain significance ★★ same condition
XRCC2 p.Ala193Pro Uncertain significance ★★ ⚠ same condition
XRCC2 p.Ala193Val Uncertain significance ★★ ⚠ same condition
XRCC2 p.Ala202Val Uncertain significance ★★ ⚠ same condition
XRCC2 p.Ala212Val Uncertain significance ★★ ⚠ same condition
XRCC2 p.Ala33Pro Uncertain significance ★★ ⚠ same condition
XRCC2 p.Ala33Thr 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/xrcc2-p-pro49 (accessed [today's date]).

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