Is RAD51C p.Pro43Ser (c.127C>T) pathogenic?

RAD51C p.Pro43Ser (c.127C>T) is classified Uncertain significance in RAD51C (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-09). AlphaMissense: likely benign (0.2867); Very rare (popmax 0.00333%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with RAD51C p.Pro43Ser (c.127C>T)?

RAD51C p.Pro43Ser (c.127C>T) is associated with hereditary neoplastic syndrome, Fanconi anemia complementation group O (ClinVar).

How common is RAD51C p.Pro43Ser (c.127C>T) in the general population?

RAD51C p.Pro43Ser (c.127C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about RAD51C p.Pro43Ser (c.127C>T)?

AlphaMissense predicts likely benign (score 0.2867) — an in-silico prediction, not a clinical call.

RAD51C p.Pro43Ser

c.127C>T · rs1442559963 · VCV490120

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2867 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2867	likely benign
REVEL	0.107	moderately benign-leaning
SaProt	LLR -9.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 1, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 42 kb · p 0.31 · regional, not allelic
Overall
CADD	23.7	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 0.00333% Admixed American · 2/60,028 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000124% 2/1,614,230 alleles · very rare exomes 2/1,461,882 · genomes 0/152,348 · 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: RAD51C
Protein: p.Pro43Ser
Coding: c.127C>T
MANE Select: NM_058216
dbSNP: rs1442559963
Type: single nucleotide variant
Location: chr17:58692770 (GRCh38)
Gene constraint: LOEUF 1.139 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.23 · 17 PDB
Residue 43: the 'required for holliday junction resolution activity' region; an α-helix

Full RAD51C 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

Also linked: Fanconi anemia complementation group O

Similar variants

RAD51C p.Pro43Ala Uncertain significance ★★ ⚠ same residue
RAD51C p.Pro43Leu Uncertain significance ★★ ⚠ same residue
RAD51C p.Pro43Thr Uncertain significance ★★ ⚠ same residue
RAD51C p.Pro43= Likely benign ★ same residue
RAD51C p.Pro43fs Likely pathogenic ★ same residue
RAD51C c.145+1G>A Pathogenic/Likely pathogenic ★★ same condition
RAD51C c.145+1G>T Pathogenic/Likely pathogenic ★★ same condition
RAD51C c.146-1G>A 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/rad51c-p-pro43ser (accessed [today's date]).

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