Is RAD54L p.Pro433= (c.1299G>A) pathogenic?

RAD54L p.Pro433= (c.1299G>A) is classified Likely benign in RAD54L (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-04-19). Low-frequency (popmax 1.32%, sas); Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with RAD54L p.Pro433= (c.1299G>A)?

RAD54L p.Pro433= (c.1299G>A) is associated with hereditary breast ovarian cancer syndrome (ClinVar).

How common is RAD54L p.Pro433= (c.1299G>A) in the general population?

RAD54L p.Pro433= (c.1299G>A) is low-frequency (popmax 1.32%, sas) (gnomAD).

How is Hereditary breast and/or ovarian cancer syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

RAD54L p.Pro433=

c.1299G>A · rs17102093 · VCV1678904

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.32%, sas)

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1	GERP -3.5
Overall
CADD	3.583	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.32% South Asian · 1,206/91,080 alleles

Filtering AF 1.26% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.24%

Overall 0.122% 1,976/1,614,106 alleles · low-frequency exomes 1,815/1,461,864 · genomes 161/152,242 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	1.32%	76
East Asian	1.29%	78
Remaining individualsnot grpmax-eligible	0.224%	447
Middle Eastern	0.033%	3,031
African / African-American	0.028%	3,572
Admixed American	0.00833%	12,002
European (non-Finnish)	0.00195%	51,304

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: RAD54L
Protein: p.Pro433=
Coding: c.1299G>A
MANE Select: NM_003579
dbSNP: rs17102093
Type: single nucleotide variant
Location: chr1:46272726 (GRCh38)
Gene constraint: LOEUF 0.94 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.64 · 1 PDB

Full RAD54L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary breast ovarian cancer syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary breast and/or ovarian cancer syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

RAD54L p.Pro433Leu Likely benign ★ ⚠ same residue
RAD54L p.Phe733Val Uncertain significance ★★ ⚠ same condition
RAD54L p.Thr508Ile Uncertain significance ★★ ⚠ same condition
RAD54L c.1042+55G>C Benign ★★ same condition
RAD54L c.1042+78G>A Benign/Likely benign ★★ same condition
RAD54L c.1611-55T>A Likely benign ★★ same condition
RAD54L c.272-21G>A Likely benign ★★ same condition
RAD54L c.767-57G>T Likely benign ★★ 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/rad54l-p-pro433 (accessed [today's date]).

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