Is RAD50 p.Ser229Arg (c.685A>C) pathogenic?

RAD50 p.Ser229Arg (c.685A>C) is classified Uncertain significance in RAD50 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-20). AlphaMissense: likely benign (0.3004); Very rare (popmax 8.48e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with RAD50 p.Ser229Arg (c.685A>C)?

RAD50 p.Ser229Arg (c.685A>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is RAD50 p.Ser229Arg (c.685A>C) in the general population?

RAD50 p.Ser229Arg (c.685A>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about RAD50 p.Ser229Arg (c.685A>C)?

AlphaMissense predicts likely benign (score 0.3004) — an in-silico prediction, not a clinical call.

RAD50 p.Ser229Arg

c.685A>C · rs1406271072 · VCV850157

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3004 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3004	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -7.31	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>G here scores Δ0.58 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.8	GERP 3.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 38 kb · p 0.02 · regional, not allelic
Overall
CADD	18.55	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 8.48e-05% European (non-Finnish) · 1/1,179,428 alleles

Overall 6.84e-05% 1/1,461,102 alleles · very rare

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.Ser229Arg
Coding: c.685A>C
MANE Select: NM_005732
dbSNP: rs1406271072
Type: single nucleotide variant
Location: chr5:132579995 (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.Ser229Asn Uncertain significance ★★ ⚠ same residue
RAD50 p.Ser229Gly Uncertain significance ★ ⚠ same residue
RAD50 p.Ser229Thr Uncertain significance ★ ⚠ same residue
RAD50 p.Ser229= Likely benign ★ same residue
RAD50 p.Ser229fs Conflicting classifications of pathogenicity ★ 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

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-ser229arg (accessed [today's date]).

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