Is RAD50 p.Phe418fs (c.1253_1254del) pathogenic?

RAD50 p.Phe418fs (c.12531254del) is classified Pathogenic in RAD50 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-04-07). Very rare (popmax 0.00719%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with RAD50 p.Phe418fs (c.1253_1254del)?

RAD50 p.Phe418fs (c.1253_1254del) is associated with hereditary neoplastic syndrome, Nijmegen breakage syndrome-like disorder (ClinVar).

How common is RAD50 p.Phe418fs (c.1253_1254del) in the general population?

RAD50 p.Phe418fs (c.1253_1254del) is very rare (popmax 0.00719%, amr) (gnomAD).

RAD50 p.Phe418fs

c.1253_1254del · rs1060501954 · VCV408373

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00719%, amr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 25
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.5	GERP 0.86, phastCons 1
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00719% Admixed American · 4/55,652 alleles

Filtering AF 0.00238% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00143%

Overall 0.000696% 11/1,580,224 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00719%	13,913
Remaining individualsnot grpmax-eligible	0.00164%	61,130
Finnishnot grpmax-eligible	0.00157%	63,646
South Asian	0.00117%	85,268
European (non-Finnish)	0.000344%	290,618

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: RAD50
Protein: p.Phe418fs
Coding: c.1253_1254del
MANE Select: NM_005732
dbSNP: rs1060501954
Type: Deletion
Location: chr5:132589637 (GRCh38)
Gene constraint: LOEUF 0.889 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 82.83 · 6 PDB

Full RAD50 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

Also linked: Nijmegen breakage syndrome-like disorder

Similar variants

RAD50 p.Phe418= Likely benign ★ same residue
RAD50 c.129+1del Pathogenic ★★ same condition
RAD50 c.3160_3164+8del Likely pathogenic ★★ same condition
RAD50 p.Arg903fs Pathogenic ★★ same condition
RAD50 p.Asn1070fs Pathogenic/Likely pathogenic ★★ same condition
RAD50 p.Asn1118fs Pathogenic/Likely pathogenic ★★ same condition
RAD50 p.Asn412fs Pathogenic ★★ same condition
RAD50 p.Asn931fs Pathogenic ★★ 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/rad50-p-phe418fs (accessed [today's date]).

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