Is RAD50 p.Pro70Ala (c.208C>G) pathogenic?

RAD50 p.Pro70Ala (c.208C>G) is classified Uncertain significance in RAD50 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-21). AlphaMissense: likely pathogenic (0.7632); Very rare (popmax 0.00112%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with RAD50 p.Pro70Ala (c.208C>G)?

RAD50 p.Pro70Ala (c.208C>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is RAD50 p.Pro70Ala (c.208C>G) in the general population?

RAD50 p.Pro70Ala (c.208C>G) is very rare (popmax 0.00112%, sas) (gnomAD).

What do computational predictors say about RAD50 p.Pro70Ala (c.208C>G)?

AlphaMissense predicts likely pathogenic (score 0.7632) — an in-silico prediction, not a clinical call.

RAD50 p.Pro70Ala

c.208C>G · VCV3942171

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7632 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00112%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.7632	likely pathogenic
REVEL	0.429	indeterminate
SaProt	LLR -9.86	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 3.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 38 kb · p 0.02 · regional, not allelic
Overall
CADD	26.0	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 0.00112% South Asian · 1/89,524 alleles

Overall 6.22e-05% 1/1,607,996 alleles · very rare exomes 1/1,455,832 · genomes 0/152,164 · joint denominator

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.Pro70Ala
Coding: c.208C>G
MANE Select: NM_005732
Type: single nucleotide variant
Location: chr5:132559362 (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.Pro70= Likely benign ★★ same residue
RAD50 p.Pro70Arg Uncertain significance ★ ⚠ same residue
RAD50 p.Pro70Leu Uncertain significance ★ ⚠ same residue
RAD50 p.Pro70Ser Uncertain significance ★ ⚠ 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-pro70ala (accessed [today's date]).

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