XRCC4

Chr 5AR

X-ray repair cross complementing 4

Also known as: SSMED, hXRCC4

NCBI Gene: 7518 ENSG00000152422 OMIM: 194363

The protein functions as a core component of non-homologous end joining DNA repair, acting as a scaffold that bridges broken DNA fragments and directly interacts with DNA ligase IV to reseal double-strand breaks during DNA repair and V(D)J recombination. Mutations cause short stature, microcephaly, and endocrine dysfunction, inherited in an autosomal recessive pattern. This condition affects growth, brain development, and endocrine function due to defective DNA repair mechanisms.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene functions together with DNA ligase IV and the DNA-dependent protein kinase in the repair of DNA double-strand breaks. This protein plays a role in both non-homologous end joining and the completion of V(D)J recombination. Mutations in this gene can cause short stature, microcephaly, and endocrine dysfunction (SSMED). Alternate transcript variants such as NM_022406 are unlikely to be expressed in some individuals due to a polymorphism (rs1805377) in the last splice acceptor site. [provided by RefSeq, Oct 2019]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.091 OMIM phenotype

Clinical Summary— XRCC4

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Gene-Disease Validity (ClinGen)

hereditary nonpolyposis colon cancer · ADLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

27 unique Pathogenic / Likely Pathogenic· 90 VUS of 197 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.09LOEUF

pLI 0.000

Z-score 1.27

OE 0.68 (0.43–1.09)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.30Z-score

OE missense 0.93 (0.82–1.07)

152 obs / 162.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.68 (0.43–1.09)

0≤0.351.4

Missense OE?0.93 (0.82–1.07)

0≤0.61.4

Synonymous OE?0.81

0≤1.21.6

LoF obs/exp: 12 / 17.8Missense obs/exp: 152 / 162.7Syn Z: 1.10

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveXRCC4-related primordial dwarfismLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6355th %ile

GOF

0.2298th %ile

LOF

0.3164th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

197 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17

Likely Pathogenic10

VUS90

Likely Benign56

Benign14

Conflicting2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	9	3	5	0	17
Likely Pathogenic	9	1	0	0	10
VUS	3	84	3	0	90
Likely Benign	0	6	22	28	56
Benign	1	3	9	1	14
Conflicting	—				2
Total	22	97	39	29	189

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

8 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap XRCC4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →