Is RAD50 p.Asp727His (c.2179G>C) pathogenic?

RAD50 p.Asp727His (c.2179G>C) is classified Uncertain significance in RAD50 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-12). AlphaMissense: likely pathogenic (0.7385); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with RAD50 p.Asp727His (c.2179G>C)?

RAD50 p.Asp727His (c.2179G>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is RAD50 p.Asp727His (c.2179G>C) in the general population?

RAD50 p.Asp727His (c.2179G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RAD50 p.Asp727His (c.2179G>C)?

AlphaMissense predicts likely pathogenic (score 0.7385) — an in-silico prediction, not a clinical call.

RAD50 p.Asp727His

c.2179G>C · VCV4678098

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7385 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.7385	likely pathogenic
REVEL	0.334	indeterminate
SaProt	LLR -9.18	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 4, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 47 kb · p 0.00013 · regional, not allelic
Overall
CADD	25.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RAD50
Protein: p.Asp727His
Coding: c.2179G>C
MANE Select: NM_005732
Type: single nucleotide variant
Location: chr5:132595782 (GRCh38)
Gene constraint: LOEUF 0.889 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 82.83 · 6 PDB
Residue 727: the zinc-hook domain; an α-helix

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.Asp727Ala 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
RAD50 c.1245+1G>A Pathogenic/Likely pathogenic ★★ same condition
RAD50 c.129+1G>A Likely pathogenic ★★ same condition
RAD50 c.129+1G>T 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-asp727his (accessed [today's date]).

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