Is RAD50 p.Ser451Arg (c.1353T>A) pathogenic?

RAD50 p.Ser451Arg (c.1353T>A) is classified Conflicting classifications of pathogenicity in RAD50 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-31). AlphaMissense: likely benign (0.1397); Very rare (popmax 0.00659%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with RAD50 p.Ser451Arg (c.1353T>A)?

RAD50 p.Ser451Arg (c.1353T>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is RAD50 p.Ser451Arg (c.1353T>A) in the general population?

RAD50 p.Ser451Arg (c.1353T>A) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about RAD50 p.Ser451Arg (c.1353T>A)?

AlphaMissense predicts likely benign (score 0.1397) — an in-silico prediction, not a clinical call.

RAD50 p.Ser451Arg

c.1353T>A · rs587782523 · VCV142528

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1397 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1397	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -7.43	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 -0.13	GERP 2.8, phastCons 0.001
Regional constraint	o/e 0.92	unconstrained · MANE · 38 kb · p 0.02 · regional, not allelic
Overall
CADD	14.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00659% South Asian · 6/91,042 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.000682% 11/1,613,256 alleles · very rare exomes 10/1,461,180 · genomes 1/152,076 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,174
European (non-Finnish)	0.000424%	235,914

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.Ser451Arg
Coding: c.1353T>A
MANE Select: NM_005732
dbSNP: rs587782523
Type: single nucleotide variant
Location: chr5:132589738 (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

Similar variants

RAD50 p.Ser451Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
RAD50 p.Ser451Cys Uncertain significance ★ ⚠ same residue
RAD50 p.Ser451Ile Uncertain significance ★ ⚠ same residue
RAD50 p.Ser451fs Pathogenic ★★ same residue
RAD50 c.1051+1G>A Likely pathogenic ★★ same condition
RAD50 c.1052-1G>A Likely pathogenic ★★ same condition
RAD50 c.1052-1G>T Pathogenic/Likely pathogenic ★★ same condition
RAD50 c.1052-2A>C Likely 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-ser451arg (accessed [today's date]).

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